Piperidines derivatives and their use as serotonin receptor antagonists

ABSTRACT

The present invention provides compounds of formula (I): which are useful for treating depression, anxiety, and alleviating the symptoms caused by withdrawal or partial withdrawal from the use of tobacco or of nicotine.

[0001] Pharmaceutical researchers have discovered that the neurons ofthe brain which contain monoamines are of extreme importance in a greatmany physiological processes which affect many psychological andpersonality-affecting processes as well. In particular, serotonin(5-hydroxytryptamine; 5-HT) has been found to be a key to a very largenumber of processes which affect both physiological and psychologicalfunctions. Drugs which influence the function of serotonin in the brainare accordingly of great importance and are now used for a large numberof different therapies.

[0002] The early generations of serotonin-affecting drugs tended to havea variety of different physiological functions, considered from both themechanistic and therapeutic points of view. For example, many of thetricyclic antidepressant drugs are now known to be active as inhibitorsof serotonin reuptake, and also to have anticholinergic, antihistaminicor anti-α-adrenergic activity. More recently, it has become possible tostudy the function of drugs at individual receptors in vitro or ex vivo,and it has also been realized that therapeutic agents free of extraneousmechanisms of action are advantageous to the patient.

[0003] The present invention provides compounds which have highlyselective activity as antagonists and partial agonists of the serotonin1_(A) receptor and a second activity as inhibitors of reuptake ofserotonin. The best-known pharmaceutical with the latter efficacy isfluoxetine, and the importance of its use in the treatment of depressionand other conditions is well documented and publicized. Artigas, TIPS,14, 262 (1993), have suggested that the efficacy of a reuptake inhibitormay be decreased by the activation of serotonin 1_(A) receptors with theresultant reduction in the firing rate of serotonin neurons.Accordingly, present research in the central nervous system is focusingon the effect of combining reuptake inhibitors with compounds whichaffect the 5-HT_(1A) receptor.

[0004] Compounds exhibiting both serotonin reuptake inhibition activityand 5-HT_(1A) antagonist activity have been described, for example, inU.S. Pat. No. 5,576,321, issued Nov. 19, 1996. Compounds of the presentinvention are potent serotonin reuptake inhibitors and antagonists ofthe 5-HT_(1A) receptor.

[0005] The present invention provides compounds of formula I:

[0006] wherein

[0007] A is hydrogen, OH or (C₁-C₆) alkoxy:

[0008] B is selected from the group consisting of:

[0009]

represents a single or a double bond;

[0010] X is hydrogen, OH or C₁-C₆ alkoxy when

represents a single bond in the piperidine ring, and X is nothing when

represents a double bond in the piperidine ring;

[0011] Y is S or CH₂;

[0012] R¹ is hydrogen, F, C₁-C₂₀ alkyl, —C(═O)NR⁸R⁹, or CN;

[0013] R² is hydrogen, F, Cl, Br, I, OH, C₁-C₆ alkyl or C₁-C₆ alkoxy;

[0014] R³ and R⁴ are each independently hydrogen or C₁-C₄ alkyl;

[0015] R⁵ and R⁶ are each independently hydrogen, F, Cl, Br, I, OH,C₁-C₆ alkyl, C₁-C₆ alkoxy, halo(C₁-C₆)alkyl, phenyl, —C(═O)NR⁸R⁹, NO₂,NH₂, CN, or phenyl substituted with from 1 to 3 substituents selectedfrom the group consisting of F, Cl, Br, I, OH, C₁-C₆ alkyl, C₁-C₆alkoxy, halo(C₁-C₆)alkyl, NO₂, NH₂, CN, and phenyl;

[0016] R⁷ is hydrogen, F, Cl, Br, I, OH, C₁-C₆ alkyl or (C₁-C₆alkyl)NR⁸R⁹;

[0017] R⁸ and R⁹ are each independently hydrogen or C₁-C₁₀ alkyl;

[0018] m is 0, 1, or 2;

[0019] n is 0, 1, or 2;

[0020] p is 0, 1, 2, 3 or 4; and

[0021] q is 0, 1, 2 or 3; or a pharmaceutically acceptable salt thereof.

[0022] The present invention further provides a method of inhibiting thereuptake of serotonin and antagonizing the 5-HT_(1A) receptor whichcomprises administering to a patient an effective amount of a compoundof formula I.

[0023] More particularly, the present invention provides a method foralleviating the symptoms caused by withdrawal or partial withdrawal fromthe use of tobacco or of nicotine; a method of treating anxiety; and amethod of treating a condition chosen from the group consisting ofdepression, hypertension, cognitive disorders, Alzheimer's disease,psychosis, sleep disorders, gastric motility disorders, sexualdysfunction, brain trauma, memory loss, eating disorders and obesity,substance abuse, obsessive-compulsive disease, panic disorder, andmigraine; which methods comprise administering to a patient an effectiveamount of a compound of formula I.

[0024] In addition, the present invention provides a method ofpotentiating the action of a serotonin reuptake inhibitor comprisingadministering to a patient an effective amount of a compound of formulaI in combination with an effective amount of a serotonin reuptakeinhibitor.

[0025] In addition, the invention provides pharmaceutical compositionsof compounds of formula I, including the hydrates thereof, comprising,as an active ingredient, a compound of formula I in combination with apharmaceutically acceptable carrier, diluent or excipient. Thisinvention also encompasses novel intermediates, and processes for thesynthesis of the compounds of formula 1.

[0026] According to another aspect, the present invention provides theuse of a compound of formula I, or a pharmaceutically acceptable saltthereof as defined hereinabove for the manufacture of a medicament forinhibiting the reuptake of serotonin and antagonizing the 5-HT_(1A)receptor.

[0027] According to yet another aspect, the present invention providesthe use of a compound of formula I or a pharmaceutically acceptable saltthereof as defined hereinabove for inhibiting the reuptake of serotoninand antagonizing the 5-HT_(1A) receptor.

[0028] It is understood that the compounds of formula Ia:

[0029] are included within the scope of the definition of formula Iwherein the substituents are defined as hereinabove.

[0030] It is further understood that the compounds of the formula Iaa:

[0031] are included within the scope of the definition of formula Iwherein the substituents are defined as hereinabove.

[0032] As used herein, the terms “Me”, “Et”, “Pr”, “iPr”, “Bu” and“t-Bu” refer to methyl, ethyl, propyl, isopropyl, butyl and tert-butyl,respectively.

[0033] As used herein, the terms “Halo”, “Halide” or “Hal” refer to achlorine, bromine, iodine or fluorine atom, unless otherwise specifiedherein.

[0034] As used herein the term “C₁-C₄ alkyl” refers to a straight orbranched, monovalent, saturated aliphatic chain of 1 to 4 carbon atomsand includes, but is not limited to methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl and the like.

[0035] As used herein the term “C₁-C₆ alkyl” refers to a straight orbranched, monovalent, saturated aliphatic chain of 1 to 6 carbon atomsand includes, but is not limited to methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl, and the like.

[0036] As used herein the term “C₁-C₁₀ alkyl” refers to a straight orbranched, monovalent, saturated aliphatic chain of 1 to 10 carbon atomsand includes, but is not limited to methyl, ethyl, propyl, isopropyl,n-butyl, isobutyl, tertiary butyl, pentyl, isopentyl, hexyl,2,3-dimethyl-2-butyl, heptyl, 2,2-dimethyl-3-pentyl, 2-methyl-2-hexyl,octyl, 4-methyl-3-heptyl and the like.

[0037] As used herein the term “C₁-C₂₀ alkyl” refers to a straight orbranched, monovalent, saturated aliphatic chain of 1 to 20 carbon atomsand includes, but is not limited to, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, 3-methylpentyl,2-ethylbutyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl,n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl,n-nonadecyl, n-eicosyl and the like.

[0038] As used herein the term “halo(C₁-C₆)alkyl” refers to a straightor branched alkyl chain having from one to six carbon atoms with 1, 2 or3 halogen atoms attached to it. Typical halo(C₁-C₆)alkyl groups includechloromethyl, 2-bromoethyl, 1-chloroisopropyl, 3-fluoropropyl,2,3-dibromobutyl, 3-chloroisobutyl, iodo-t-butyl, trifluoromethyl andthe like. The term “halo(C₁-C₆)alkyl” includes within its definition theterm “halo(C₁-C₄)alkyl”.

[0039] As used herein the term “C₁-C₆ alkoxy” refers to a straight orbranched alkyl chain having from one to six carbon atoms attached to anoxygen atom. Typical C₁-C₆ alkoxy groups include methoxy, ethoxy,propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and the like. The term“C₁-C₆ alkoxy” includes within its definition the term “C₁-C₄ alkoxy”.

[0040] The designation “

” refers to a bond that protrudes forward out of the plane of the page.

[0041] The designation “

” refers to a bond that protrudes backward out of the plane of the page.

[0042] This invention includes the hydrates and the pharmaceuticallyacceptable salts of the compounds of formula I. A compound of thisinvention can possess a sufficiently basic functional group which canreact with any of a number of inorganic and organic acids, to form apharmaceutically acceptable salt.

[0043] The term “pharmaceutically acceptable salt” as used herein,refers to salts of the compounds of formula I which are substantiallynon-toxic to living organisms. Typical pharmaceutically acceptable saltsinclude those salts prepared by reaction of the compounds of the presentinvention with a pharmaceutically acceptable mineral or organic acid.Such salts are also known as acid addition salts. Such salts include thepharmaceutically acceptable salts listed in Journal of PharmaceuticalScience, 66, 2-19 (1977) which are known to the skilled artisan.

[0044] Acids commonly employed to form acid addition salts are inorganicacids such as hydrochloric acid, hydrobromic acid, hydroiodic acid,sulfuric acid, phosphoric acid, and the like, and organic acids such asp-toluenesulfonic, methanesulfonic acid, benzenesulfonic acid, oxalicacid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citricacid, benzoic acid, acetic acid, and the like. Examples of suchpharmaceutically acceptable salts are the sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, bromide, iodide,acetate, propionate, decanoate, caprate, caprylate, acrylate, ascorbate,formate, hydrochloride, dihydrochloride, isobutyrate, caproate,heptanoate, propiolate, propionate, phenylpropionate, salicylate,oxalate, malonate, succinate, suberate, sebacate, fumarate, malate,maleate, hydroxymaleate, mandelate, nicotinate, isonicotinate,cinnamate, hippurate, nitrate, phthalate, teraphthalate,butyne-1,4-dioate, butyne-1,4-dicarboxylate, hexyne-1,4-dicarboxylate,hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate,hydroxybenzoate, methoxybenzoate, dinitrobenzoate, oacetoxybenzoate,naphthalene-2-benzoate, phthalate, p-toluenesulfonate,p-bromobenzenesulfonate, p-chlorobenzenesulfonate, xylenesulfonate,phenylacetate, trifluoroacetate, phenylpropionate, phenylbutyrate,citrate, lactate, α-hydroxybutyrate, glycolate, tartrate,benzenesulfonate, methanesulfonate, ethanesulfonate, propanesulfonate,hydroxyethanesulfonate, naphthalene-1-sulfonate,napththalene-2-sulfonate, mandelate, tartarate, and the like. Preferredpharmaceutically acceptable acid addition salts are those formed withmineral acids such as hydrochloric acid and hydrobromic acid, and thoseformed with organic acids such as maleic acid, oxalic acid andmethanesulfonic acid.

[0045] It should be recognized that the particular counterion forming apart of any salt of this invention is usually not of a critical nature,so long as the salt as a whole is pharmacologically acceptable and aslong as the counterion does not contribute undesired qualities to thesalt as a whole. It is further understood that such salts may exist as ahydrate.

[0046] As used herein, the term “stereoisomer” refers to a compound madeup of the same atoms bonded by the same bonds but having differentthree-dimensional structures which are not interchangeable. Thethree-dimensional structures are called configurations. As used herein,the term “enantiomer” refers to two stereoisomers whose molecules arenonsuperimposable mirror images of one another. The term “chiral center”refers to a carbon atom to which four different groups are attached. Asused herein, the term “diastereomers” refers to stereoisomers which arenot enantiomers. In addition, two diastereomers which have a differentconfiguration at only one chiral center are referred to herein as“epimers”. The terms “racemate”, “racemic mixture” or “racemicmodification” refer to a mixture of equal parts of enantiomers.

[0047] The term “enantiomeric enrichment” as used herein refers to theincrease in the amount of one enantiomer as compared to the other. Aconvenient method of expressing the enantiomeric enrichment achieved isthe concept of enantiomeric excess, or “ee”, which is found using thefollowing equation:${ee} = {\frac{E^{1} - E^{2}}{E^{1} + E^{2}} \times 100}$

[0048] wherein E¹ is the amount of the first enantiomer and E² is theamount of the second enantiomer. Thus, if the initial ratio of the twoenantiomers is 50:50, such as is present in a racemic mixture, and anenantiomeric enrichment sufficient to produce a final ratio of 50:30 isachieved, the ee with respect to the first enantiomer is 25%. However,if the final ratio is 90:10, the ee with respect to the first enantiomeris 80%. An ee of greater than 90% is preferred, an ee of greater than95% is most preferred and an ee of greater than 99% is most especiallypreferred. Enantiomeric enrichment is readily determined by one ofordinary skill in the art using standard techniques and procedures, suchas gas or high performance liquid chromatography with a chiral column.Choice of the appropriate chiral column, eluent and conditions necessaryto effect separation of the enantiomeric pair is well within theknowledge of one of ordinary skill in the art. In addition, theenantiomers of compounds of formulas I or Ia can be resolved by one ofordinary skill in the art using standard techniques well known in theart, such as those described by J. Jacques, et al., “Enantiomers,Racemates, and Resolutions”, John Wiley and Sons, Inc., 1981.

[0049] Some of the compounds of the present invention have one or morechiral centers and may exist in a variety of stereoisomericconfigurations. As a consequence of these chiral centers, the compoundsof the present invention occur as racemates, mixtures of enantiomers andas individual enantiomers, as well as diastereomers and mixtures ofdiastereomers. All such racemates, enantiomers, and diastereomers arewithin the scope of the present invention.

[0050] The terms “R” and “S” are used herein as commonly used in organicchemistry to denote specific configuration of a chiral center. The term“R” (rectus) refers to that configuration of a chiral center with aclockwise relationship of group priorities (highest to second lowest)when viewed along the bond toward the lowest priority group. The term“S” (sinister) refers to that configuration of a chiral center with acounterclockwise relationship of group priorities (highest to secondlowest) when viewed along the bond toward the lowest priority group. Thepriority of groups is based upon their atomic number (in order ofdecreasing atomic number). A partial list of priorities and a discussionof stereochemistry is contained in “Nomenclature of Organic Compounds:Principles and Practice”, (J. H. Fletcher, et al., eds., 1974) at pages103-120.

[0051] The specific stereoisomers and enantiomers of compounds offormula (I) can be prepared by one of ordinary skill in the artutilizing well known techniques and processes, such as those disclosedby Eliel and Wilen, “Stereochemistry of Organic Compounds”, John Wiley &Sons, Inc., 1994, Chapter 7, Separation of Stereoisomers. Resolution.Racemization, and by Collet and Wilen, “Enantiomers, Racemates, andResolutions”, John Wiley & Sons, Inc., 1981. For example, the specificstereoisomers and enantiomers can be prepared by stereospecificsyntheses using enantiomerically and geometrically pure, orenantiomerically or geometrically enriched starting materials. Inaddition, the specific stereoisomers and enantiomers can be resolved andrecovered by techniques such as chromatography on chiral stationaryphases, enzymatic resolution or fractional recrystallization of additionsalts formed by reagents used for that purpose.

[0052] As used herein, the term “SRI” refers to serotonin reuptakeinhibitor.

[0053] As used herein the term “serotonin” is equivalent to andinterchangeable with the terms “5-HT” or “5-hydroxytryptamine”.

[0054] As used herein, “Pg” refers to a protecting group on the aminewhich is commonly employed to block or protect the amine while reactingother functional groups on the compound. Examples of protecting groups(Pg) used to protect the amino group and their preparation are disclosedby T. W. Greene, “Protective Groups in Organic Synthesis,” John Wiley &Sons, 1981, pages 218-287. Choice of the protecting group used willdepend upon the substituent to be protected and the conditions that willbe employed in subsequent reaction steps wherein protection is required,and is well within the knowledge of one of ordinary skill in the art.Preferred protecting groups are t-butoxycarbonyl also known as the BOCprotecting group, and benzyloxycarbonyl.

[0055] The compounds of formula I can be prepared by techniques andprocedures readily available to one of ordinary skill in the art. Forexample, various starting materials and general procedures which may beemployed by one of ordinary skill in the art in the preparation ofcompounds of formula I are described in U.S. Pat. No. 3,929,793, issuedDec. 30, 1975, U.S. Pat. No. 4,304,915, issued Dec. 8, 1981, U.S. Pat.No. 4,288,442, issued Sep. 8, 1981, U.S. Pat. No. 4,361,562, issued Nov.30, 1982, U.S. Pat. No. 4,460,586, issued Jul. 17, 1984, U.S. Pat. No.4,704,390, issued Nov. 3, 1987, U.S. Pat. No. 4,935,414, issued Jun. 19,1990, U.S. Pat. No. 5,013,761, issued May 7, 1991, and U.S. Pat. No.5,614,523, issued Mar. 25, 1997. More specifically, compounds of formulaI can be prepared by following the procedures as set forth in Schemes Ithrough IV. All substituents, unless otherwise indicated, are previouslydefined. The reagents and starting materials are readily available toone of ordinary skill in the art. More specifically, Schemes I throughII provide general syntheses of various intermediate piperidines.

[0056] In Scheme I, step A, compound (1) is added to piperidone (2)under conditions well known in the art, to provide the alcohol (3). Forexample, an appropriately substituted naphthalene, such as2-bromonaphthalene, 1-bromo-5-methoxy-naphthalene,2-bromo-7-methoxy-naphthalene, 6-iodo-1-methoxy-naphthalene, and thelike, is dissolved in a suitable organic solvent, such astetrahydrofuran and cooled to about −78° C. To this stirring solution isadded an excess of a suitable base, such as t-butyllithium. The mixtureis stirred for about 1 to 3 hours, and 1.0 to about 1.1 equivalents ofthe piperidone (2) are added. The reaction is allowed to warm to roomtemperature and the alcohol (3) is isolated and purified by techniqueswell known in the art. For example, the mixture is diluted with waterand extracted with a suitable organic solvent, such as ethyl acetate.The organic extracts are combined, washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under vacuum. Thecrude alcohol can then be purified by flash chromatography on silica gelwith a suitable eluent, such as ethyl acetate/hexane to provide thepurified alcohol (3). Alternatively, the crude isolated alcohol (3) canbe carried directly onto the next step.

[0057] The piperidones (2) are readily available to one of ordinaryskill in the art utilizing known starting materials. For example, I.V.Micovic, et al., J. Chem. Soc., Perkin Trans., 1(16), 2041-2050 (1996)teach the preparation of variously substituted piperidine-2,4-diones.Such piperidine-2,4-diones can be selectively protected, alkylated, andreduced under conditions well known in the art to provide the desiredpiperidone (2). For example, compounds of the formula (2a′)

[0058] can be prepared in a manner analogous to the procedure describedby Micovic et al. above, which can then be reduced to provide the2,2-disubstituted-N-protected-4-piperidone (2a″).

[0059] In Scheme I, step B, the alcohol (3) is dehydrated under standardconditions to provide the 1,2,5,6-tetrahydropiperidine (4) wherein Pg′is maintained as a protecting group and does not represent hydrogen. Forexample, the alcohol (3) is dissolved in a suitable organic solvent,such as toluene, and treated with an excess of a suitable acid, such ap-toluenesulfonic acid monohydrate. The reaction mixture is heated atreflux for about 6 to 12 hours and then cooled. The1,2,5,6-tetrahydropiperidine is then isolated and purified underconditions well known in the art. For example, the cooled reactionmixture is basified with 2 N sodium hydroxide and extracted with asuitable organic solvent, such as ethyl acetate. The organic extractsare combined, washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated under vacuum. The crude residue is thenpurified by flash chromatography on silica gel with a suitable eluent,such as methanol/methylene chloride to provide the purified1,2,5,6-tetrahydropiperidine (4).

[0060] Alternatively, in Scheme I, step B the alcohol (3) can bedehydrated and deprotected concomitantly under standard conditions toprovide the compound (4) wherein Pg′ is hydrogen. For example, alcohol(3) wherein the protecting group is N-t-butoxycarbonyl, is dissolved ina suitable organic solvent, such as dry dichloromethane and the solutionis cooled to about 0° C. To this solution is added excesstrifluoroacetic acid and the reaction mixture is stirred at about 0° C.for about 15 h. The reaction is then quenched at room temperature withsaturated aqueous NaHCO₃ solution. The product is then isolated bytechniques well known in the art, such as extraction, and then purifiedby flash chromatography. For example, the mixture is extracted with asuitable organic solvent, such as dichloromethane, the combined organicextracts are dried over anhydrous magnesium sulfate, filtered andconcentrated under vacuum to provide the crude compound (4). Thismaterial can be purified by flash chromatography on silica gel with asuitable eluent, such as ethyl acetate/hexane.

[0061] In Scheme I, step C, the 1,2,5,6-tetrahydropiperidine (4) ishydrogenated under conditions well known in the art to provide a mixtureof piperidines (5a) and (5b). For example, the1,2,5,6-tetrahydropiperidine (4) is dissolved in a suitable organicsolvent, such as ethanol and treated with a suitable catalyst, such as5% palladium on carbon. The mixture is then placed under an atmosphereof hydrogen and stirred for about 12 hours at room temperature. Thereaction mixture is then filtered to remove the catalyst and thefiltrate is concentrated under vacuum to provide a mixture of isomers(5a) and (5b). It is readily appreciated by one of ordinary skill in theart that various isomers may exist at this step wherein the R groups canbe either cis or trans to the naphthyl group. It is further recognizedthat these isomers may be separated from one another by techniques wellknown in the art, such as flash chromatography, radial chromatography orhigh performance liquid chromatography on silica gel with a suitableeluent, such as methanol/methylene chloride. Alternatively, the mixtureof isomers may be carried on to the next step or the separated isomersmay individually be carried on to the next step.

[0062] In Scheme I, step D, wherein Pg′ is a protecting group and nothydrogen, the piperidines (5a) and (5b) are deprotected under conditionswell known to one of ordinary skill in the art to provide piperidines(6a) and (6b). For example, when Pg is a methyl group, the piperidines(5a) and (5b) are dissolved in a suitable organic solvent, such asdichloroethane and cooled to about 0° C. The cooled solution is thentreated with an excess of 1-chloroethylchloroformate. The reaction isthen allowed to warm to room temperature and then heated at reflux forabout 12 hours. After cooling, the solvent is then removed under vacuumand the residue is dissolved in a suitable organic solvent, such asmethanol. The solution is then heated at reflux for about 2 to 4 hours,cooled to room temperature, and then concentrated under vacuum. Theresidue is treated with water and a suitable organic solvent, such asethyl acetate. The phases are separated and the aqueous phase isextracted with ethyl acetate. The organic extracts, including the firstorganic phase, are combined, rinsed with brine, dried over anhydroussodium sulfate, filtered and concentrated under vacuum to provide thecrude piperidines (6a) and (6b). The mixture can then be separated intopurified individual stereoisomers if they were not already separated instep C using similar techniques, such as flash chromatography, radialchromatography or high performance chromatography on silica gel with asuitable eluent, such as methanol/methylene chloride.

[0063] It is readily appreciated by one of ordinary skill in the artthat the sequence of steps of dehydration, deprotection, and reductioncan be varied depending upon the protecting groups utilized and theultimate products desired. The conditions required for varying thesequence are well within the knowledge of one of ordinary skill in theart.

[0064] In Scheme IA, the steps A through D are carried out in a manneranalogous to the procedures set forth in Scheme 1, steps A through Drespectively.

[0065] In Scheme IB, alcohol (3a) is alkylated under standard conditionsto provide the ether (3b). For example, alcohol (3a), wherein theprotecting group is N-t-butoxycarbonyl, is dissolved in a suitableorganic solvent, such as dry MeOH and the solution is cooled to about 0°C. To this solution is added excess trifluoroacetic acid. The reactionmixture is then stirred at room temperature for about one to 6 days. Thereaction is then quenched at room temperature with saturated aqueousNaHCO₃ solution, extracted with a suitable organic solvent such asdichloromethane, the combined organic extracts are dried over anhydrousmagnesium sulfate, filtered and concentrated under vacuum to provide thecrude ether (3b). The crude ether (3b) can then be purified by flashchromatography on silica gel with a suitable eluent, such as 7% (10%conc. NH₄OH in MeOH)/CH₂Cl₂.

[0066] In Scheme IC, alcohol (3a) can be deprotected without dehydrationunder standard conditions well known in the art, through appropriatechoice of protecting groups, to provide the deprotected alcohol (3b′).For example, the alcohol (3a), wherein the protecting group is a—CH₂CH═CH₂ group, is dissolved in a suitable solvent, such as aqueousethanol (10% H₂O). The solution is then treated withchlorotris(triphenylphosphine) rhodium(I) (Wilkinson's catalyst) andapproximately 50% of the solvent is then distilled off over a period ofabout 1 hour. An additional 65 mL of solvent and 45 mg of Wilkinson'scatalyst is added and the reaction mixture is refluxed for about 1 hourand then the solvent is again distilled off to about 50% volume. Thereaction mixture is then evaporated and the residue is purified usingsilica gel chromatography with a suitable eluent, such asdichloromethane/20% methanol, 2% anhydrous ammonia in dichloromethanegradient, to provide the purified deprotected alcohol (3b′).

[0067] In Scheme II, step A, a naphthylboronic acid (7), such as2-naphthylboronic acid is combined with the 1,2,5,6-tetrahydropiperidine(8) to provide the coupled compound (9). For example, about 1 to 1.5equivalents of a naphthylboronic acid (7) is combined with about 1equivalent of 1,2,5,6-tetrahydropiperidine (8), about 2 equivalents oflithium chloride, a catalytic amount oftetrakis(triphenylphosphine)palladium(0) in a mixture of 2 M aqueoussodium carbonate and tetrahydrofuran. The mixture is heated at refluxfor about 12 hours and then cooled to room temperature. The reaction isthen treated with 2 N sodium hydroxide and extracted with a suitableorganic solvent, such as ethyl acetate. The organic extracts arecombined, rinsed with brine, dried over anhydrous sodium sulfate,filtered and concentrated under vacuum. The crude residue is thenpurified by flash chromatography on silica gel with a suitable eluentsuch as ethyl acetate/hexane to provide the compound (9).

[0068] In Scheme II, step B, compound 9 is hydrogenated under standardconditions to provide the piperidines (10a) and (10b). For example,compound (9) is dissolved in a suitable organic solvent, such asmethanol, treated with a suitable catalyst, such as 5% palladium oncarbon and stirred under an atmosphere of hydrogen for about 12 hours atroom temperature. The reaction mixture is then filtered to remove thecatalyst and the filtrate is concentrated under vacuum to providepiperidines (10a) and (10b). As noted in Scheme I, step C, it is readilyappreciated by one of ordinary skill in the art that various isomers mayexist at this particular step wherein the R groups can be either cis ortrans to the naphthyl group. It is further recognized that these isomersmay be separated from one another by techniques well known in the art,such as flash chromatography, radial chromatography or high performanceliquid chromatography on silica gel with a suitable eluent, such asmethanol/methylene chloride. Alternatively, the mixture of isomers maybe carried on to the next step or the separated isomers may individuallybe carried onto the next step.

[0069] In Scheme II, step C, the piperidines (10a) and (10b) aredeprotected under conditions well known in the art to provide thepiperidines (6a) and (6b). For example, piperidines (10a) and (10b) aredissolved in a suitable solvent mixture, such as 50% water/isopropanoland treated with an excess of a suitable base, such as potassiumhydroxide. The reaction mixture is then heated at reflux for about 1 to3 days and then cooled to room temperature. 2 N sodium hydroxide isadded and the reaction is extracted with a suitable organic solvent,such as ethyl acetate. The organic extracts are combined, rinsed withbrine, dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum. The crude residue is then purified by flash chromatographyon silica gel with a suitable eluent, such as methanol/methylenechloride to provide the purified piperidines (6a) and (6b). The mixturecan then be separated into individual stereoisomers if they were notalready separated in step C using similar techniques, such as flashchromatography, radial chromatography or high performance chromatographyon silica gel with a suitable eluent, such as methanol/methylenechloride.

[0070] It is readily appreciated by one of ordinary skill in the artthat compounds (4), (4′) and (9) can be deprotected prior to reductionand the unsaturated deprotected piperidines can be used directly inSchemes III and IV.

[0071] In Scheme IIA, step A, a 2-halo-benzothiazole (11), such as2-chloro-4-fluorobenzothiazole, is combined with the1,2,5,6-tetrahydropiperidine (8), to provide the coupled compound (9′).For example, about 1 equivalent of a 2-halo-benzothiazole (11) iscombined with about 1.2 equivalents of 1,2,5,6-tetrahydropiperidine (8),about 1 equivalent of bis(trimethyltin), about 3 equivalents of lithiumchloride, and a catalytic amount oftetrakis(triphenylphosphine)palladium(0) in a suitable organic solvent,such as 1,4-dioxane. The mixture is heated at reflux for about 20 hoursand then cooled to about 20° C. The reaction is then treated withsaturated potassium fluoride and ethyl acetate, and stirred for about 2hours. The organic phase is separated, washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under vacuum. Thecrude residue is then purified by flash chromatography on silica gelwith a suitable eluent such as ethyl acetate/hexane to provide thecompound (9′).

[0072] In Scheme IIA, Step B, compound (9′) is deprotected understandard conditions to provide compound (12). For example, compound (9′)is dissolved in a suitable organic solvent, such as dichloromethane,cooled to about 0° C. and treated with an excess of trifluoroaceticacid. The mixture is then stirred for about 30 minutes, then warmed toabout 20° C. and stirred for an additional 20 minutes. The mixture isthen diluted with 2 N sodium hydroxide and extracted with a suitableorganic solvent, such as ethyl acetate. The organic extracts arecombined, dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum to provide the crude compound (12). Compound (12) can thenbe purified by flash chromatography on silica gel with a suitableeluent, such as (dichloromethane/10% methanol 1% ammonium hydroxide indichloromethane gradient elution) to provide the purified compound (12).

[0073] In Scheme IIA, step C, compound (12) is hydrogenated understandard conditions to provide the cis and trans isomers (6a″) and(6b″). For example, compound (12) is dissolved in a suitable organicsolvent, such as ethanol and treated with a catalytic amount of platinumoxide. The mixture is then hydrogenated under 1 atmosphere for about 20hours, filtered and the filtrate concentrated under vacuum to providethe cis and trans isomers (6a″) and (6b″). The compounds can then beseparated using standard techniques well known to one of ordinary skillin the art, such as recrystallization techniques, flash chromatographyor chiral chromatography.

[0074] It is readily appreciated by one of ordinary skill in the artthat piperidines of structure (16) [see Schemes III and IV below],wherein B represents:

[0075] can be prepared under standard conditions, such as in a manneranalogous to the procedures set forth in Schemes I through IIA forpreparation of the piperidines described therein.

[0076] Compounds of formula I are prepared following generally theprocedure set forth in Scheme III. All substituents, unless otherwiseindicated, are previously defined. The reagents and starting materialsare readily available to one of ordinary skill in the art.

[0077] In Scheme III, step A, compound (13) is coupled with compound(14) under standard conditions well known in the art, to providecompound (15). For example, compound (13) is dissolved in a suitableorganic solvent, such as DMF, and treated with about one equivalent of asuitable base, such as sodium hydride. To the stirring solution is addedabout 1.1 equivalents of compound (14) and the reaction is stirred atabout −10° C. to room temperature for about 20 minutes to 1 hour.Compound (15) is then isolated and purified by techniques well known inthe art, such as extraction techniques and flash chromatography. Forexample, the reaction mixture is diluted with water and extracted with asuitable organic solvent, such as ethyl acetate. The organic extractsare combined, dried over anhydrous magnesium sulfate, filtered andconcentrated under vacuum to provide the crude material. The crudematerial can be purified by flash chromatography on silica gel with asuitable eluent, such as ethyl acetate/hexane.

[0078] In Scheme III, step B compound (15) is coupled with piperidine(16) under standard conditions well known in the art to provide thecompound of formula 1. For example, compound (15) is dissolved in asuitable organic solvent, such as dimethylformamide with about oneequivalent of a suitable neutralizing agent, such as sodium bicarbonate.To this mixture is added about one equivalent of a piperidine (16) andthe mixture is heated at about 70° C. to 90° C. for about 4 hours to 12hours. The compound of formula I is then isolated and purified bytechniques well known in the art, such as extraction techniques andflash chromatography. For example, the reaction mixture is diluted withwater and extracted with a suitable organic solvent, such as ethylacetate. The organic extracts are combined, washed with water and brine,dried over anhydrous magnesium sulfate, filtered and concentrated undervacuum to provide the crude material. The crude material can be purifiedby flash chromatography on silica gel with a suitable eluent, such asethyl acetate/hexane.

[0079] Compounds of formula Ia are prepared following generally theprocedure set forth in Scheme IV. All substituents, unless otherwiseindicated, are previously defined. The reagents and starting materialsare readily available to one of ordinary skill in the art.

[0080] In Scheme IV, step A, the compound of structure (13) is coupledwith the epoxide (17) to provide the epoxide (18). For example, compound(13) is dissolved in a suitable organic solvent, such asdimethylformamide and cooled to 0° C. About 1.1 equivalents of sodiumhydride is added to the solution which is then stirred for about onehour. A solution of one equivalent of the epoxide (17) indimethylformamide is then added dropwise to the solution. The reactionmixture is then stirred for about 1 to 24 hours at 0° C. It is thenquenched with water. The resulting solution is extracted with a suitableorganic solvent, such as ethyl acetate. The organic layers are combined,washed with water, dried over anhydrous magnesium sulfate, filtered andconcentrated to provide crude epoxide (18). The crude product can bepurified by crystallization with a suitable solvent, such asdichloromethane or by flash chromatography on silica gel with a suitableeluent, such as dichloromethane/hexane.

[0081] In Scheme IV, step B, the epoxide (18) is opened with thesubstituted piperidine of structure (16) under standard conditions wellknown in the art, such as those disclosed by Krushinski, et al. in U.S.Pat. No. 5,576,321, issued Nov. 19, 1996, to provide the compound offormula Ia. For example, epoxide (18), such as(S)-(+)-4-(oxiranylmethoxy)-1H-indole is dissolved in a suitable organicsolvent, such as methanol, and treated with about one equivalent ofpiperidine (16). The solution is then heated to reflux for about 8 to 12hours and then cooled to room temperature. The reaction mixture is thenconcentrated under vacuum and the crude residue is purified andresulting stereoisomers separated from each other by techniques wellknown in the art, such as flash chromatography, radial chromatography orhigh performance liquid chromatography on silica gel with a suitableeluent, such as methanol/methylene chloride.

[0082] The following examples are illustrative only and representtypical syntheses of the compounds of formula I and formula Ia asdescribed generally above. The reagents and starting materials arereadily available to one of ordinary skill in the art. As used herein,the following terms have the meanings indicated: “eq” or “equiv.” refersto equivalents; “g” refers to grams; “mg” refers to milligrams; “L”refers to liters; “mL” refers to milliliters; “μL” refers tomicroliters; “mol” refers to moles; “mmol” refers to millimoles; “psi”refers to pounds per square inch; “min” refers to minutes; “h” refers tohours; “° C.” refers to degrees Celsius; “TLC” refers to thin layerchromatography; “HPLC” refers to high performance liquid chromatography;“R_(f)” refers to retention factor; “R_(t)” refers to retention time;“δ”refers to parts per million down-field from tetramethylsilane; “THF”refers to tetrahydrofuran; “DMF” refers to N,N-dimethylformamide; “DMSO”refers to methyl sulfoxide; “LDA” refers to lithium diisopropylamide;“aq” refers to aqueous; “EtOAc” refers to ethyl acetate; “iPrOAc” refersto isopropyl acetate; “MeOH” refers to methanol; “MTBE” refers totert-butyl methyl ether, and “RT” refers to room temperature.

Preparation 1

[0083] Preparation of 1-Bromo-5-methoxy-naphthalene.

[0084] Preparation of 5-Bromo-3,4-dihydro-1(2H)-naphthalenone and7-Bromo-3,4-dihydro-1(2H)-naphthalenone.

[0085] Anhydrous AlCl₃ (66.67 g, 0.50 mol, 99.99%) under N₂ was stirredvigorously as 1-tetralone (29.83 g, 0.20 mol) was added dropwise over −7min. The evolved HCl gas was scrubbed through 5 N NaOH. The resultingmixture was a dark brown oil that exothermed to 75° C. When thetemperature had cooled to 50° C., Br₂ was added dropwise over 15 min.The mixture, which had cooled further to 40° C., was heated to 80° C.for 5 min, then poured into a mixture of ice (600 g) and 12 N HCl (80mL). All the ice melted, leaving a cool dark mixture which was dilutedwith H₂O (200 mL) and extracted with CH₂Cl₂ (200 mL, 100 mL). Thecombined extracts were dried with MgSO₄ and concentrated in vacuo(30-60° C.) to a dark brown oil (45.6 g; theory=45.02 g).

[0086] Chromatography over silica gel 60 with 8:1 heptane:THF did notprove effective, but two passes through the Biotage radially pressuredsilica gel cartridges using 9:1 heptane:MTBE as eluent producedacceptably pure fractions.

[0087] 5-Bromo-3,4-dihydro-1(2H)-naphthalenone was isolated as an orangeoil (12.27 g, 28.3%). HPLC showed an apparent wide divergence inabsorbances at 230 nm for the two regioisomers, and was therefore notreliable for a potency check. TLC on silica gel (4:1 heptane:MTBE)confirmed modest contamination with7-bromo-3,4-dihydro-1(2H)-naphthalenone.

[0088] 7-Bromo-3,4-dihydro-1(2H)-naphthalenone was isolated as ayellowish-white solid (15.48 g, 35.8%); mp 69.5-75° C. (lit 74-75° C.).¹H NMR (CDCl₃) corresponded to the literature description, plus a traceof heptane and an undefined by-product. TLC showed it to be cleaner than5-bromo-3,4-dihydro-1 (2H)-naphthalenone.

[0089] A third fraction of orange oil (9.06 g, 20.9%) was isolated. TLCshowed it to be a nearly 1:1 ratio of5-bromo-3,4-dihydro-1(2H)-Naphthalenone, and7-bromo-3,4-dihydro-1(2H)-Naphthalenone.

[0090] Preparation of 2,5-Dibromo-3,4-dihydro-1(2H)-naphthalenone.

[0091] A clear yellow solution of5-bromo-3,4-dihydro-1(2H)-Naphthalenone(12.09 g, 53.7 mmol) in freshlyopened Et₂O (220 mL) under an N₂ atmosphere was chilled to −5° C. HClwas bubbled in subsurface for 1 min, causing no visible change. Thedropwise addition of a solution of Br₂ (8.58 g, 53.7 mmol) in CH₂Cl₂ (20mL) and Et₂O (2 mL) to the vigorously stirring solution of5-bromo-3,4-dihydro-1(2H)-naphthalenone over 2 h (each drop was allowedto fully decolorize before adding the next) produced a product mixturethat assayed by HPLC. Peak area showed 79.4% title compound, 9.5%unreacted 5-bromo-3,4-dihydro-1(2H)-naphthalenone, 0.6% unidentified,and 9.4% 2,2,5-tribromo-1-tetralone. The addition of H₂O produced a toplight brown organic phase, and a clear, colorless bottom aqueous phasewhich was separated. After drying with MgSO₄, the organic layer wasconcentrated in vacuo at room temperature to give the crude intermediatetitle compound as a light brown oil (16.08 g, 98.5%).

[0092] Preparation of 5-Bromo-1-naphthalenol.

[0093] The crude mixture of 2,5-dibromo-1-tetralone (16.08 g, 52.9mmol,), LiCl (5.61 g, 132 mmol), and 120 mL of dry DMF were combinedunder an N₂ atmosphere and heated to reflux (˜155° C.). The mixtureturned dark brown. HPLC showed complete consumption of the startingmaterial in just 0.5 h. After cooling to room temperature, the mixturewas diluted with 1 N HCl (200 mL) and extracted three times with Et₂O(100 mL, 25 mL, 25 mL). The Et₂O layers were combined to give a brownhazy mixture (some emulsion). After stirring with decolorizing carbon(10 g, Calgon ADP) and filtration through hyflo supercel, a clear lightyellow solution was obtained. This solution was extracted with 3 N NaOH(100 mL, 25 mL), leaving the non-naphtholic byproducts behind. The brownNaOH extracts were combined, acidified to pH 1 with conc. HCl, andextracted with CH₂Cl₂ (100 mL, 25 mL). The combined CH₂Cl₂ layers formeda deep red solution. After stirring with decolorizing carbon (5 g, DarcoG-60) and filtration through hyflo supercel, the solution was againlight yellow. An equal volume of heptane was added, and the CH₂Cl₂ wasdistilled away. When the temperature reached 75° C., gray precipitatebecame evident. This increased substantially on cooling to roomtemperature. Following filtration and drying in vacuo at 50° C., aproduct mixture of gray solid (5.92 g, 50.2%) was obtained. HPLC showedthis to be a mixture of 7-bromo-1-naphthol (48.3%) and5-bromo-1-naphthol (50.8%). However, ¹H NMR (CDCl₃) integration showedthat the actual ratio was about 9/15-Br/7-Br. Preparative reverse phaseHPLC gave one peak of 5-bromo-1-naphthol as a white solid (3.22 g,27.3%).

[0094] Preparation of the Final Title Compound.

[0095] Purified 5-bromo-1-naphthol (3.22 g, 14.4 mmol), was dissolved inCH₃CN (50 mL), giving a clear and nearly colorless solution.Dimethylsulfate (2.72 g, 21.6 mmol, 1.5 equiv), K₂CO₃ (3.0 g, 21.6mmol), and tetrabutylammonium bromide (TBAB, 20 mg) as phase transfercatalyst were added, and the resulting mixture was stirred for 16 h.HPLC revealed no detectable starting material, so H₂O (50 mL) was added.The inorganic salt promptly dissolved, followed immediately bycrystallization of the product. Following filtration, an H₂O wash (50mL) of the cake, and drying in vacuo at 50° C., provided the final titlecompound as a light tan crystalline solid (3.07 g, 90.0%) in outstandingpurity: mp 68.5-69.5° C. Clean ¹H and ¹³C NMR (CDCl₃) spectra.Satisfactory elemental analysis was obtained when block dried at 60° C.Purity of 99.6% by HPLC.

Preparation 2

[0096] Preparation of 2-Bromo-7-methoxy-naphthalene.

[0097] Preparation of 7-Bromo-2-naphthalenol.

[0098] Triphenyl phosphine (89.7 g, 0.342 mol) and acetonitrile (350 mL)were combined in a 1-L flask under N₂ atmosphere. The mixture was cooledto 10° C. Bromine (17.6 mL, 0.342 mol) was added dropwise over 10minutes. The cooling bath was removed and 2,7-dihydroxynaphthalene (50.0g, 0.312 mol) was added along with 350 mL of CH₃CN rinse. The resultingyellow tan mixture was heated at reflux for 3 hours. Acetonitrile wasdistilled off using a water aspirator over 2 hours resulting in agrayish white solid. The solid was heated to 280° C. over 30 minutesgiving a black liquid. The liquid was heated to 310° C. over 20 minutesand the temperature was maintained at 310° C. for an additional 15minutes until gas evolution ceased. The black mixture was cooled to roomtemperature. Chromatography yielded 34.5 g of the intermediate titlecompound as an off-white solid which was 87% pure by HPLC (43% yield).

[0099] Preparation of the Final Title Compound.

[0100] 2-Bromo-7-hydroxynaphthalene (34.1 g, 0.134 mol), DMF (290 mL)and powdered potassium carbonate (31.8 g, 0.230 mol) were combined in a500-mL flask under N₂ atmosphere. Methyl iodide (14.3 mL, 0.230 mol) wasadded at once and the dark yellow mixture was stirred vigorously at roomtemperature for 3¾ hours. Water (290 mL) was added dropwise over 15minutes to induce crystallization. The mixture was stirred at roomtemperature for 1 hour. The product was filtered off and washed with 200mL of a 1:1 mixture of DMF and water. The solid was dried in vacuo at50° C. to yield 32.6 g of pale yellow solid (HPLC: 89%). The solid wasdissolved in 300 mL of boiling MeOH. The hot solution was filtered, thenplaced in the freezer overnight. The resulting crystals were filteredand washed with 100 mL of cold MeOH. The solid was dried in vacuo at 50°C. to give 27.0 g of pale yellow solid (HPLC: 95%). The solid wasdissolved in 100 mL of boiling i-PrOH then allowed to cool to roomtemperature.

[0101] The resulting solid was filtered and washed with 100 mL ofi-PrOH. The solid was dried in vacuo at 50° C. to yield 22.8 g of thetitle compound as pale yellow crystals.

Preparation 3

[0102] Preparation of 6-Iodo-1-methoxy-naphthalene.

[0103] Preparation of 5-Bromo-2-naphthalenecarboxylic Acid.

[0104] 2-Naphthoic acid (50.0 g, 0.290 mol), glacial acetic acid (250mL), bromine (15 mL, 0.291 mol) and iodine (1.3 g, 0.005 mol) werecombined in a flask under N₂ atmosphere. The mixture was heated atreflux for 35 minutes then cooled to room temperature. The thick yellowmixture was stirred at room temperature for 1 hour. The mixture wasfiltered and the pale orange solid was rinsed with ˜100 mL of thefiltrate. The solid was dried in vacuo at 55° C. overnight to yield 55.5g of pale orange solid. The solid was slurried in 275 mL of 1 N NaOH for30 minutes. The solid was filtered off and rinsed 3 times with 50 mLportions of the filtrate. The solid was air dried in the hood over theweekend to yield 46.7 g of solid. The solid was added to 220 mL ofwater. Concentrated HCl (15 mL) was added to obtain pH of 1.3 and themixture was stirred for 4 hours. The solid was filtered off and washedwith 200 mL of water.

[0105] The solid was dried in vacuo at 50° C. to give 37.6 g ofintermediate title compound as white crystals (HPLC: 90% with 9%2-naphthoic acid, 46% yield).

[0106] Preparation of 5-Bromo-2-naphthalenecarboxylic Acid, MethylEster.

[0107] 5-Bromo-2-naphthoic acid (17.33 g, 69 mmol) and 250 mL of MeOHwere combined in a flask under N₂ atmosphere. Thionyl chloride (5.84 mL,80 mmol) was added dropwise over 15 minutes at a temperature of 25-30°C. resulting in a pale yellow mixture. The mixture was heated at refluxfor 3¼ hours. The resulting yellow solution was concentrated in vacuo to137.4 g of solution then placed in the freezer overnight. The resultingthick mixture was filtered and the solid was washed with 100 mL of coldMeOH. The solid was dried in vacuo at 50° C. to give 11.39 g ofintermediate title compound as white crystals. A second crop wasfiltered and washed with 100 mL of cold MeOH. The solid was dried to1.31 g of white crystals. Yield: 69%, 2 crops.

[0108] Preparation of 5-Methoxy-2-naphthoic Acid.

[0109] A 25% solution of sodium methoxide in MeOH (63 mL, 0.258 mol) wasadded to a 500-mL flask under N₂ atmosphere. Cupric iodide(recrystallized, 4.19 g, 22 mmol), 160 mL of pyridine, 160 mL of MeOHand methyl 5-bromo-2-naphthoate (11.39 g, 43 mmol) were added to theflask to give a yellow green mixture. The mixture was heated at refluxfor 30 hours. The mixture was cooled to room temperature and water (850mL) was added resulting in a rust colored mixture having pH of 12.8. ThepH was adjusted to 1.0 by addition of concentrated HCl resulting in awhite precipitate. The mixture was cooled to 10° C., filtered and thesolid was washed with cold water. The solid was dried to 11.03 g whitecrystals. The solid was taken up in 200 mL of EtOAc and 150 mL of water.The pH of the mixture was 3.5. The pH was adjusted to 10.0 by additionof 5 N NaOH and maintained for 4 hours. The EtOAc was removed byconcentration in vacuo then the pH was adjusted to 1.0 by addition ofconcentrated HCl. The mixture was placed in a freezer overnight. Themixture was filtered and the solid was washed with water until thefiltrate stream was colorless. The solid was dried in vacuo at 50° C. togive 9.77 g of off-white solid. The solid was added to 50 mL of 2.5 NNaOH and the thick orange mixture was stirred for 3 hours. The pH wasadjusted to 1.0 with concentrated HCl. The mixture was filtered and thesolid was washed with water. The solid was dried to 9.43 g of off-whitesolid. The solid was dissolved in 200 mL of boiling MeOH and the hotsolution was filtered then cooled to room temperature. Water (300 mL)was added and the mixture was stirred at room temperature for 2 hours.The solid was filtered off and washed with 100 mL of a 1:1 mixture ofMeOH and water. The solid was dried in vacuo at 50° C. to give 7.18 g ofintermediate title compound as a white solid (HPLC: 97%, 83% yield).

[0110] Preparation of 5-Methoxy-2-Naphthylamine.

[0111] 5-Methoxy-2-naphthoic acid (3.17 g, 15.7 mmol), CH₂CO₂ (38 mL)and DMF (3.04 mL, 39.2 mmol) were combined in a 50-mL flask under a N₂atmosphere. Oxalyl chloride (2.73 mL, 31.3 mmol) was added dropwise over30 minutes at 20 to 23° C. The resulting yellow solution was stirred atroom temperature for 15 minutes. The solution was then concentrated invacuo to 6.48 g of yellow solid which was slightly wet with DMF. Thesolid was dissolved in CH₃CN (157 mL) and added dropwise over 35 minutesto a solution of sodium azide (2.55 g, 39.2 mmol) in 24 mL of water, andrinsed in with an additional 25 mL of CH₃CN. Analysis of the resultingyellow mixture by HPLC after 5 minutes showed 15% acyl chlorideremaining. Water (15 mL) was added to give an orange mixture and topromote acyl azide formation. The mixture was heated at reflux for 1hour and 40 minutes. The mixture was cooled to room temperature.

[0112] Sodium hydroxide (50 mL, 2N solution) was added and the resultingyellow mixture was stirred at room temperature overnight. The mixturewas concentrated in vacuo to 102.0 g of brown gum plus liquid. Themixture was extracted with 50 mL of CH₂Cl₂. The CH₂Cl₂ layer was driedover Na₂SO₄, filtered and concentrated in vacuo to provide 1.83 g of theintermediate title compound as a brown oil (HPLC: 91%, 61% yield).

[0113] Preparation of the Final Title Compound.

[0114] 2-Amino-5-methoxynaphthalene (1.78 g, 9.35 mmol), 5 mL ofconcentrated HCl(aq), 5 mL of water and 10 g of ice were combined in aflask.

[0115] The tan orange mixture was cooled to 5° C. A chilled solution ofsodium nitrite (0.75 g, 10.8 mmol) in 4 mL of water was added over 5minutes keeping the temperature below 10° C. The mixture was stirred at5° C. for 30 minutes. A solution of potassium iodide (1.71 g, 10.3 mmol)in 10.5 mL of water was added, the bath was removed and the orangesolution plus black solid was stirred at room temperature. Analysis byHPLC showed that more KI was needed. Potassium iodide (7.2 g, 43.4mmol), 100 mL of CH₃CN and 50 mL of acetone were added and the mixturewas stirred for 22 hours at room temperature. The mixture was extractedwith 150 mL of Et₂O. The Et₂O phase was washed successively with 200 mLof 5% NaHSO_(3(aq)), 200 mL of 5% NaHCO_(3(aq)), 200 mL of water and 200mL of saturated NaCl solution. The Et₂O phase was dried over Na₂SO₄,filtered and concentrated in vacuo to yield 2.21 g of dark brown solid(HPLC: 69.5%). The solid was adsorbed onto 8.0 g of silica gel 60 inCH₂Cl₂ then concentrated to a powder. The powder was slurried in hexaneand chromatographed on 100 g of silica gel 60 at atmospheric pressure,eluting with hexane. The desired final title compound was collected(1.33 g, 50% yield) as a white solid after concentration of theappropriate fractions.

Preparation 4

[0116] Preparation of N-(t-Butyloxycarbonvi)-2-methyl-4-piperidone.

[0117] A solution of the following protected amine;

[0118] (145 g, prepared in a manner analogous to the proceduresdescribed by Hall, H. K. Jr., J. Am. Chem. Soc., 79, 5444 (1957) andHarper, N. J.; Beckett, A. H.; Balon, A. D. J., J. Chem. Soc., 2704(1960)) dissolved in THF (200 mL) was added dropwise over one hour to acooled solution of potassium t-butoxide (58.9 g) in THF (500 mL). Themixture was stirred at 0° C. for 2.5 hours and then warmed to roomtemperature over 1 hours with stirring. Another 50 mL of 1.0 M potassiumt-butoxide in THF was added. After one hour, the solvent was removedunder vacuum and the residue was dissolved in ethyl acetate (1 L). Theorganic solution was washed with saturated ammonium chloride (2×500 mL)which was back extracted with ethyl acetate (2×500 mL). The organicextracts were combined, dried over anhydrous magnesium sulfate, filteredand concentrated under vacuum to provide 120. 6 g of crude material asan oil. This oil was then treated with 5 N HCl (700 mL) at reflux forabout 14.5 hours. After cooling, the solution was rinsed with a mixtureof ethyl acetate/diethyl ether (1:1, 2×300 mL). The aqueous layer wasthen concentrated to provide the piperidone salt of structure:

[0119] The above piperidone salt was then dissolved in water (200 mL)and THF (250 mL). The solution was then cooled to 0° C. and treated with50% sodium hydroxide (35 mL) followed by dropwise addition oftert-butoxycarbonyl anhydride (106.7 g) in THF (100 mL) over one hour.The ice bath was then removed and the solution was stirred at roomtemperature for about 4 days. The pH was then adjusted to about 8 to 9.The THF was then removed under vacuum and the mixture is taken up inethyl acetate (500 mL). The layers were separated and the aqueous layerwas extracted with ethyl acetate (2×500 mL). The organic extracts werecombined, washed with brine (300 mL), dried over anhydrous magnesiumsulfate, filtered and concentrated under vacuum. The residue waspurified by chromatography on silica gel (ethyl acetate/hexanes) toprovide 36.81 g of title compound.

Preparation 5

[0120] Preparation of N-(t-Butyloxycarbonyl)-2,2-dimethyl-4-piperidone

[0121] In a manner analogous to the procedure described in preparation 4above, the title compound can be prepared from the following startingmaterial;

Preparation 6

[0122] Preparation of N-Benzyl-3,3-dimethyl-4-piperidone.

[0123] In a 1 liter 3-neck flask equipped with a mechanical stirrer, anaddition funnel and a calcium chloride drying tube was added a 37%weight solution of formaldehyde (168.5 mL, 2.25 mole) dissolved in 500mL of absolute ethanol.

[0124] The resulting solution was cooled in an ice-water bath to 10° C.,and benzylamine (109 mL, 1 mole) was added dropwise over a one hourperiod. In a separate 3-liter 3-neck flask equipped with a mechanicalstirrer, an addition funnel and two condensers was added3-methyl-2-butanone (113 mL, 1.06 mole) dissolved in 500 ml of absoluteethanol and concentrated hydrogen chloride (92 mL, 1.11 mole). Theresulting solution was brought to reflux and theformaldehyde/benzylamine solution is added dropwise over a 2 hourperiod. This solution was heated at reflux overnight, and then cooled toambient temperature. Diisopropylethylamine (142.2 g, 1.1 mole) andformaldehyde (22.46 mL, 0.3 mole) were added and the resulting solutionwas heated to reflux for six hours, and then cooled to ambienttemperature. The solution was quenched with potassium hydroxide (61.6 g,1.1 mole) in 200 mL of water, and then extracted 3 times with 500 mlethyl acetate. The organic layers were concentrated under vacuum to give225 g of a red oil. The crude oil was dissolved in 1 liter of methylenechloride. This solution was carefully poured over 1 kg of silica gel ona sintered glass filter. The silica gel was washed with 4 L of methylenechloride. The methylene chloride was concentrated under vacuum toprovide 142 g of a yellow oil which was crystallized in a freezerovernight. Yield=65.4%.

[0125] MS(ion spray)=218.3 (M+1)

EXAMPLE 1

[0126] Preparation of(2S)-(−)-1-(4-Benzo[b]thiophenox)-3-(4-(3-methylbenzo[b]thiophen-2-yl)piperidin-1-yl)-2-propanolOxalate.

[0127] Preparation of4-Hydroxy-4-(3-Methylbenzo[b]thiophen-2-yl)-1-(2-Propenyl)-piperidine.

[0128] Scheme IA, step A: To a solution of 3-methylbenzothiophene (2.863g, 19.3 mmol) in tetrahydrofuran (80 mL) at −78° C. was added a solutionof n-butyllithium (13.3 mL, 21.2 mmol, 1.6 M in hexanes). The solutionwas warmed to 0° C. for one hour then recooled to −78° C. A solution of1-(2-propenyl)-4-piperidone (2.957 g, 21.2 mmol) in tetrahydrofuran wasadded dropwise and the mixture was warmed to 20° C. After stirring for18 hours at 20° C. the mixture was diluted with brine and extracted 3times with ethyl acetate. The combined organics were dried over sodiumsulfate then filtered and evaporated. The residue was purified usingsilica gel chromatography (dichloromethane/5% methanol indichloromethane gradient eluent) to give 4.61 g (83%) of theintermediate title compound as a white amorphous solid. FDMS m/e=288(M⁺+1).

[0129] Preparation of4-Hydroxy-4-(3-methylbenzo[b]thiophen-2-yl)piperidine.

[0130] Scheme IC: To a solution of4-hydroxy-4-(3-methylbenzo[b]thiophen-2-yl)-1-(2-propenyl)piperidine(2.821 g, 9.81 mmol) in aqueous ethanol (65 mL, 10% H₂O) was addedchlorotris(triphenylphosphine) rhodium(I) (Wilkinson's catalyst) (45 mg,0.0486 mmol). Approximately 50% of the solvent was distilled off over aperiod of 1 hour. An additional 65 mL of solvent and 45 mg ofWilkinson's catalyst was added. The mixture was refluxed for 1 hour andthen the solvent was distilled off to about 50% volume. The mixture washeated at reflux and the residue was purified using silica gelchromatography (dichloromethane/20% methanol, 2% anhydrous ammonia indichloromethane gradient eluent) to give 1.55 g (64%) of theintermediate title compound as an amorphous white powder. FDMS m/e=248(M⁺+1).

[0131] Preparation of the Final Title Compound.

[0132] Scheme IV, Step B: A solution4-hydroxy-4-(3-methylbenzo[b]thiophen-2-yl)piperidine (0.078 g, 0.337mmol) and (S)-(+)-4-(oxiranylmethoxy)benzo[b]-thiophene (0.070 g, 0.337mmol) in methanol (3 mL) was heated at reflux for 18 hours and thencooled and evaporated. The residue was purified using silica gelchromatography (dichloromethane/2% methanol in dichloromethane gradientelution) to give the free base of the title compound as a clearcolorless oil (0.081 g, 55%). The oxalate salt was prepared to give thetitle compound. FDMS m/e=438 (M⁺+1 of free base). [α]_(D)=−1.99(c=0.502, methanol). C₂₅H₂₇NO₂S₂.C₂H₂O₄ analysis: Calculated found C61.46 61.73 H 5.54 5.48 N 2.65 2.67

EXAMPLE 2

[0133] Preparation of(2S)-(−)-1-(4-Benzo[b]thiophenoxy)-3-(4-(3-ethylbenzo[b]thiophen-2-yl)piperidin-1-yl)-2-propanolOxalate.

[0134] Preparation of 3-(1-Hydroxyethyl)benzorbithiophene.

[0135] To a solution of 3-acetyl thianaphthene (2.024 g, 11.5 mmol) inethanol (15 mL) was added sodium borohydride (0.434 g, 11.5 mmol). Themixture was stirred at 20° C. for 4 hours then evaporated, diluted withbrine and extracted 3 times with ethyl acetate. The combined organicswere dried over sodium sulfate, filtered and evaporated to give theintermediate title compound as a clear oil (1.924 g, 94%) which was usedas is in subsequent reactions. FDMS m/e=178 (M⁺).

[0136] Preparation of4-Hydroxy-4-(3-(1-hydroxyethyl)benzo[b]thiophen-2-yl)-1-(t-butyloxycarbonyl)piperidine.

[0137] Scheme IA, Step A: To a solution of3-(1-hydroxyethyl)benzo[b]thiophene (2.036 g, 11.4 mmol) intetrahydrofuran (75 mL) at −78° C. was added a solution ofn-butyllithium (15.7 mL, 25.1 mmol, 1.6 M in hexanes). The solution waswarmed to 0° C. for one hour then recooled to −78° C. A solution of1-t-butyloxycarbonyl-4-piperidone (2.503 g, 12.6 mmol) intetrahydrofuran was added dropwise and the mixture was warmed to 20° C.After stirring for 6 hours at 20° C. the mixture was diluted with brineand extracted 3 times with ethyl acetate. The combined organics weredried over sodium sulfate then filtered and evaporated. The residue waspurified using silica gel chromatography (dichloromethane/5% methanol indichloromethane gradient eluent) to give 3.75 g (87%) of theintermediate title compound as a yellow amorphous solid. FDMS m/e=378(M⁺+1).

[0138] Preparation of4-(3-Ethylbenzo[b]thiophen-2-yl)-1,2,5,6-tetrahydropyridine.

[0139] Scheme IA, Step B:4-Hydroxy-4-(3-(1-hydroxyethyl)benzo[b]thiophen-2-yl)-1-(t-butyloxycarbonyl)piperidine(1.038 g, 2.75 mmol) was slowly added in portions to trifluoroaceticacid (6 mL). To this mixture was added triethylsilane (1.0 mL, 6.05mmol) dropwise. The solution was stirred at 20° C. for 3 hours thendiluted with 2 N sodium hydroxide and extracted 3 times with ethylacetate. The combined organics were dried over sodium sulfate, filteredand evaporated. The residue was chromatographed (dichloromethane/20%methanol, 2% anhydrous ammonia in dichloromethane gradient eluent) togive the intermediate title compound as a yellow solid (0.484 g, 72%).FDMS m/e=244 (M⁺+1).

[0140] Preparation of 4-(3-Ethylbenzo[b]thien-2-yl)piperidine.

[0141] Scheme IA, Step C: To a mixture of4-(3-ethylbenzo[b]thiophen-2-yl)-1,2,5,6-tetrahydropyridine (0.465 g,1.91 mmol) in ethanol (15 mL) and 2,2,2-trifluoroethanol (5 mL) wasadded 10% palladium on carbon (0.25 g). The mixture was hydrogenated atone atmosphere for 24 hours. The mixture was carefully filtered andevaporated to give the intermediate title compound as a yellow amorphoussolid (0.395 g, 84%). FDMS m/e=246 (M⁺+1).

[0142] Preparation of the Final Title Compound.

[0143] Scheme IV, Step B: A solution4-hydroxy-4-(3-ethylbenzo[b]thiophen-2-yl)piperidine (0.069 g, 0.281mmol) and (S)-(+)-4-(oxiranylmethoxy)-benzo[b]thiophene (0.058 g, 0.281mmol) in methanol (3 mL) was heated at reflux for 18 hours and thencooled and evaporated. The residue was purified using silica gelchromatography (dichloromethane/1% methanol in dichloromethane) to givethe free base of the final title compound as a clear colorless oil(0.050 g, 39%). The oxalate salt was prepared to give the titlecompound. FDMS m/e=452 (M⁺+1 of free base). C₂₆H₂₉NO₂S₂.C₂H₂O₄ analysis:Calculated found C 62.09 62.29 H 5.77 5.52 N 2.59 2.58

EXAMPLE 3

[0144] Preparation of(2S)-(−)-1-(4-Benzo[b]thiophenoxy)-3-(4-(6-fluoronaphth-2-yl)-1,2,5,6-tetrahydropyrid-1-yl)-2-propanoloxalate.

[0145] Scheme IV, Step B: A solution4-(6-fluoronaphth-2-yl)-1,2,5,6-tetrahydropyridine (0.094 g, 0.414 mmol)and (S)-(+)-4-(oxiranylmethoxy)-benzo[b]thiophene (0.085 g, 0.414 mmol)in methanol (4 mL) was refluxed for 18 hours and then cooled andevaporated. The residue was purified using silica gel chromatography(dichloromethane/2% methanol in dichloromethane gradient elution) togive the free base of the title compound as a yellow oil (0.130 g, 73%).The oxalate salt was prepared to give the title compound. FDMS m/e=434(M⁺+1 of free base). [α]_(D)=−7.75 (c=0.516, methanol).C₂₈H₂₄FNO₂S.C₂H₂O₄ analysis: Calculated found C 64.23 63.83 H 5.01 4.92N 2.68 2.30

EXAMPLE 4

[0146] Preparation of(2S)-(−)-1-(4-Benzo[b]thiophenoxy)-3-(4-(6-fluoronaphth-2-yl)Piperidin-1-yl)-2-propanol.

[0147] Scheme IV, Step B: A solution 4-(6-fluoronaphth-2-yl)piperidine(0.069 g, 0.301 mmol) and (S)-(+)-4-(oxiranylmethoxy)benzo[b]thiophene(0.062 g, 0.301 mmol) in methanol (3 mL) was heated at reflux for 18hours and then cooled and evaporated. The residue was purified usingsilica gel chromatography (dichloromethane/5% methanol indichloromethane gradient elution) to give the title compound as a whiteamorphous solid (0.066 g, 50%). FDMS m/e 436 (M⁺+1). C₂₆H₂₆FNO₂S.analysis: Calculated found C 71.70 71.77 H 6.02 5.83 N 3.22 3.16

[0148] Serotonin 1_(A) Receptor Activity

[0149] The compounds of the present invention are active at theserotonin ¹A receptor, particularly as antagonists and as partialagonists at that receptor, and are distinguished by their selectivity.It is now well understood by pharmacologists and physicians thatpharmaceuticals which have a single physiological activity, or which aremuch more active in the desired activity than in their other activities,are much more desirable for therapy than are compounds which havemultiple activities at about the same dose.

[0150] The 5-HT_(1A) receptor binding potency of the present compoundsare measured by a modification of the binding assay described by Taylor,et al. (J. Pharmacol. Exp. Ther. 236, 118-125, 1986); and Wong, et al.,Pharm. Biochem. Behav. 46, 173-77 (1993). Membranes for the bindingassay are prepared from male Sprague-Dawley rats (150-250 g). Theanimals are killed by decapitation, and the brains are rapidly chilledand dissected to obtain the hippocampi. Membranes from the hippocampiare either prepared that day, or the hippocampi are stored frozen (−70°C.) until the day of preparation. The membranes are prepared byhomogenizing the tissue in 40 volumes of ice-cold Tris-HCl buffer (50mM, pH 7.4 at 22° C.) using a homogenizer for 15 sec., and thehomogenate is centrifuged at 39800×g for 10 min. The resulting pellet isthen resuspended in the same buffer, and the centrifugation andresuspension process is repeated three additional times to wash themembranes. Between the second and third washes the resuspended membranesare incubated for 10 min. at 37° C. to facilitate the removal ofendogenous ligands. The final pellet is resuspended in 67 mM Tris-HCl,pH 7.4, to a concentration of 2 mg of tissue original wet weight/200 μL.This homogenate is stored frozen (−70° C.) until the day of the bindingassay. Each tube for the binding assay has a final volume of 800 μL andcontains the following: Tris-HCl (50 mM), pargyline (10 μM), CaCl₂ (3mM), [³H]8-OH-DPAT (1.0 nM), appropriate dilutions of the drugs ofinterest, and membrane resuspension equivalent to 2 mg of originaltissue wet weight, for a final pH of 7.4. The assay tubes are incubatedfor either 10 min. or 15 min. at 37° C., and the contents are thenrapidly filtered through GF/B filters (pretreated with 0.5%polyethylenimine), followed by four one-mL washes with ice-cold buffer.The radioactivity trapped by the filters is quantitated by liquidscintillation spectrometry, and specific [³H]8-OH-DPAT binding to the5-HT_(1A) sites is defined as the difference between [3H]8-OH-DPAT boundin the presence and absence of 10 μM 5-HT.

[0151] IC₅₀ values, i.e., the concentration required to inhibit 50% ofthe binding, are determined from 12-point competition curves usingnonlinear regression (SYSTAT, Inc., Evanston, Ill.). IC₅₀ values areconverted to KI values using the Cheng-Prusoff equation (Biochem.Pharmacol., 22, 3099-3108 (1973)).

[0152] Additional binding assays of some of the present compounds arecarried out by an assay method which uses a cloned cell line whichexpresses the serotonin 1A receptor, rather than the hippocampalmembranes. Such cloned cell lines have been described by Fargin, et al.,J. Bio. Chem., 264,14848-14852 (1989), Aune, et al., J. Immunology,151,1175-1183 (1993), and Raymond, et al., Naunyn-Schmiedeberg's Arch.Pharmacol., 346,127-137 (1992). Results from the cell line assay aresubstantially in agreement with results from the hippocampal membraneassay.

[0153] As was reported by R. L. Weinshank, et al., WO93/14201, the5-HT_(1A) receptor is functionally coupled to a G-protein as measured bythe ability of serotonin and serotonergic drugs to inhibit forskolinstimulated cAMP production in NIH3T3 cells transfected with the5-HT_(1A) receptor. Adenylate cyclase activity is determined usingstandard techniques. A maximal effect is achieved by serotonin. An Emaxis determined by dividing the inhibition of a test compound by themaximal effect and determining a percent inhibition. (N. Adham, et al.,supra,; R. L. Weinshank, et al., Proceedings of the National Academy ofSciences (USA), 89,3630-3634 (1992)), and the references cited therein.

[0154] Measurement of cAMP Formation

[0155] Transfected NIH3T3 cells (estimated Bmax from one pointcompetition studies=488 fmol/mg of protein) are incubated in DMEM, 5 mMtheophylline, 10 mM HEPES (4-[2-hydroxyethyl]-1-piperazineethanesulfonicacid) and 10 μM pargyline for 20 minutes at 37° C., 5% carbon dioxide.Drug dose-effect curves are then conducted by adding 6 different finalconcentrations of drug, followed immediately by the addition offorskolin (10 mM). Subsequently, the cells are incubated for anadditional 10 minutes at 37° C., 5% carbon dioxide. The medium isaspirated and the reaction is stopped by the addition of 100 mMhydrochloric acid. To demonstrate competitive antagonism, adose-response curve for 5-HT is measured in parallel, using a fixed doseof methiothepin (0.32 mM). The plates are stored at 4° C. for 15 minutesand then centrifuged for 5 minutes at 500×g to pellet cellular debris,and the supernatant is aliquoted and stored at −20° C. before assessmentof cAMP formation by radioimmunoassay (cAMP radioimmunoassay kit;Advanced Magnetics, Cambridge, Mass.). Radioactivity is quantified usinga Packard COBRA Auto Gamma counter, equipped with data reductionsoftware. Representative compounds are tested for 5-HT_(1A) receptorantagonist activity in the cAMP assay.

[0156] 5HT_(1A) Antagonist, In Vivo Tests

[0157] a) 5HT_(1A) Antagonism Subcutaneous Test

[0158] Compounds are tested over a range of subcutaneous doses foractivity in blocking the 8-OH-DPAT induced behaviors and hypothermia.Lower lip retraction (LLR) and flat body posture (FBP) are recorded inmale Sprague Dawley rats (˜250 grams from Harlan Sprague Dawley). BothLLR and FBP are measured on a scale of 0-3 (Wolff et al, 1997). In theLLR behavioral assay, “0” indicates normal lip position; “1” indicates aslight separation of the lips; “2” indicates that the lips are open withsome teeth visible; “3” indicates that the lips are fully open with allthe front teeth exposed. In the FBP assay, a score of “0” indicatesnormal body posture; “1” indicates that the stomach is on the floor withthe back in its normal rounded position; “2” indicates that the stomachis on the floor with the back straightened and rising from the shouldersto the hips; “3” indicates that the stomach is pressed into the floorand the back is flattened with the shoulders and hips even. Core bodytemperature is recorded by rectal probe inserted 5.0 cm immediatelyafter the behavioral measures. Rats are injected subcutaneous withcompound (at 0, 0.3, 1.0 and 3.0 mg/kg) 35 minutes before scoring andthe 8-OH-DPAT (0.1 mg/kg subcutaneous) is injected 20 minutes beforescoring.

[0159] b) 5HT₁A Agonist Subcutaneous Test

[0160] The compounds are also tested at a high dose of 10 mg/kgsubcutaneous alone to see if they induced 5HT_(1A) agonist-likehypothermia.

[0161] The efficacy of the compounds of the invention to inhibit thereuptake of serotonin is determined by a paroxetine binding assay, theusefulness of which is set out by Wong, et al., Neuropsychopharmacology,8, 23-33 (1993). Synaptosomal preparations from rat cerebral cortex aremade from the brains of 100-150 g Sprague-Dawley rats which are killedby decapitation. The cerebral cortex is homogenized in 9 volumes of amedium containing 0.32 M sucrose and 20 μM glucose. The preparations areresuspended after centrifugation by homogenizing in 50 volumes of coldreaction medium (50 μM sodium chloride, 50 μM potassium chloride, pH7.4) and centrifuging at 50,000 g for 10 minutes. The process isrepeated two times with a 10-minute incubation at 37° C. between thesecond and third washes. The resulting pellet is stored at −70° C. untiluse. Binding of ³H-paroxetine to 5-HT uptake sites is carried out in 2mL reaction medium containing the appropriate drug concentration, 0.1 nM³H-paroxetine, and the cerebral cortical membrane (50 μg protein/tube).Samples are incubated at 37° C. for 30 minutes; those containing 1 μMfluoxetine are used to determine nonspecific binding of ³H-paroxetine.After incubation, the tubes are filtered through Whatman GF/B filters,which are soaked in 0.05% polyethylenimine for 1 hour before use, usinga cell harvester by adding about 4 mL cold Tris buffer (pH 7.4),aspirating, and rinsing the tubes three additional times. Filters arethen placed in scintillation vials containing 10 mL scintillation fluid,and the radioactivity is measured by liquid scintillationspectrophotometry.

[0162] The pharmacological activities which have been describedimmediately above provide the mechanistic basis for the pharmaceuticalutility of the compounds described in this document. A number ofpharmaceutical utilities will be described below. The activity of thecompounds at the serotonin 1_(A) receptor provides a method of affectingthe serotonin 1_(A) receptor which comprises administering to a patientin need of such treatment an effective amount of a compound offormula 1. Reasons for the necessity of affecting the serotonin 1_(A)receptor will be described in detail below, but in all cases the effecton the serotonin ¹ A 0.15 receptor is brought about through thecompounds' potency as antagonists or partial agonists at that receptor.A patient in need of a modification of the effects of the 5-HT_(1A)receptor is one having one or more of the specific conditions andproblems to be further described, or a condition or problem not yetrecognized as created by an imbalance or malfunction of the 5-HT_(1A)receptor, since research on the central nervous system is presentlyongoing in many fields and newly discovered relationships betweenreceptors and therapeutic needs are continually being discovered. In allcases, however, it is the compounds' ability to affect the serotonin1_(A) receptor which creates their physiological or therapeutic effects.

[0163] Further, the activity of compounds of formula I in the inhibitionof the reuptake of serotonin provides a method of inhibiting thereuptake of serotonin comprising administering to a patient in need ofsuch treatment an effective amount of a compound of that formula. Thetreatment of depression with drugs of the class of which fluoxetine isthe leader has become perhaps the greatest medical breakthrough of thepast decade. Numerous other treatment methods carried out by theadministration of the compounds of formula I will be set out in detailbelow.

[0164] The unique combination of 5-HT_(1A) receptor activity andserotonin reuptake inhibition possessed by the compounds of theinvention afford a method of providing to a patient both physiologicalactivities with a single administration of a compound of that formula.As discussed in the Background section of this document, the value ofcombining the two effects has been discussed in the literature, and itis believed that the present compounds are advantageous in that theyprovide both physiological effects in a single drug. It is presentlybelieved that the result of administration of a compound of formula I isto provide physiological and therapeutic treatment methods which aretypical of those provided by presently known serotonin reuptakeinhibitors, but with enhanced efficacy and quicker onset of action.

[0165] The activities of compounds of formula I at the 5-HT_(1A)receptor and in reuptake inhibition are of comparable potencies, so aneffective amount as defined hereinabove for affecting the serotonin1_(A) receptor or for inhibiting the reuptake of serotonin, is effectivefor affecting the serotonin 1_(A) receptor and for inhibiting thereuptake of serotonin in a patient.

[0166] Further discussion of specific therapeutic methods provided bythe dual activity compounds of formula I, and the diseases andconditions advantageously treated therewith, are provided below.

[0167] The compounds of the present invention are useful for binding,blocking or modulating the serotonin receptor, and for the treatment ofconditions caused by or influenced by defective function of thatreceptor. In particular, the compounds are useful for antagonism at theserotonin 1_(A) receptor, and accordingly, are useful for the treatmentof conditions caused by or affected by excessive activity of thatreceptor.

[0168] More particularly, the compounds are useful in the treatment ofanxiety, depression, hypertension, cognitive disorders, Alzheimer'sdisease, psychosis, sleep disorders, gastric motility disorders, sexualdysfunction, brain trauma, memory loss, appetite disorders, bulimia,obesity, substance abuse, obsessive-compulsive disease, panic disorderand migraine.

[0169] Depression in its many variations has recently become much morevisible to the general public than it has previously been. It is nowrecognized as an extremely damaging disorder, and one that afflicts asurprisingly large fraction of the human population. Suicide is the mostextreme symptom of depression, but millions of people, not quite sodrastically afflicted, live in misery and partial or completeuselessness, and afflict their families as well by their affliction. Theintroduction of fluoxetine was a breakthrough in the treatment ofdepression, and depressives are now much more likely to be diagnosed andtreated than they were only a decade ago.

[0170] Depression is often associated with other diseases andconditions, or caused by such other conditions. For example, it isassociated with Parkinson's disease; with HIV; with Alzheimer's disease;and with abuse of anabolic steroids. Depression may also be associatedwith abuse of any substance, or may be associated with behavioralproblems resulting from or occurring in combination with head injuries,mental retardation or stroke. Depression in all its variations is apreferred target of treatment with the compounds of the presentinvention.

[0171] Obsessive-compulsive disease appears in a great variety ofdegrees and symptoms, generally linked by the victim's uncontrollableurge to perform needless, ritualistic acts. Acts of acquiring, ordering,cleansing and the like, beyond any rational need or rationale, are theoutward characteristic of the disease. A badly afflicted patient may beunable to do anything but carry out the rituals required by the disease.Fluoxetine is approved in the United States and other countries for thetreatment of obsessive-compulsive disease and has been found to beeffective.

[0172] Obesity is a frequent condition in the American population. Ithas been found that fluoxetine will enable an obese patient to loseweight, with the resulting benefit to the circulation and heartcondition, as well as general well being and energy.

[0173] Urinary incontinence is classified generally as stress or urgeincontinence, depending on whether its root cause is the inability ofthe sphincter muscles to keep control, or the overactivity of thebladder muscles.

[0174] The present treatment methods are useful for treating many otherdiseases, disorders and conditions as well, as set out below. In manycases, the diseases to be mentioned here are classified in theInternational Classification of Diseases, 9th Edition (ICD), or in theDiagnostic and Statistical Manual of Mental Disorders, 3rd VersionRevised, published by the American Psychiatric Association (DSM). Insuch cases, the ICD or DSM code numbers are supplied below for theconvenience of the reader.

[0175] depression, ICD 296.2 & 296.3, DSM 296, 294.80, 293.81, 293.82,293.83, 310.10, 318.00, 317.00

[0176] migraine

[0177] pain, particularly neuropathic pain

[0178] bulimia, ICD 307.51, DSM 307.51

[0179] premenstrual syndrome or late luteal phase syndrome, DSM 307.90

[0180] alcoholism, ICD 305.0, DSM 305.00 & 303.90

[0181] tobacco abuse, ICD 305.1, DSM 305.10 & 292.00

[0182] panic disorder, ICD 300.01, DSM 300.01 & 300.21

[0183] anxiety, ICD 300.02, DSM 300.00

[0184] post-traumatic syndrome, DSM 309.89

[0185] memory loss, DSM 294.00

[0186] dementia of aging, ICD 290

[0187] social phobia, ICD 300.23, DSM 300.23

[0188] attention deficit hyperactivity disorder, ICD 314.0

[0189] disruptive behavior disorders, ICD 312

[0190] impulse control disorders, ICD 312, DSM 312.39 & 312.34

[0191] borderline personality disorder, ICD 301.83, DSM 301.83

[0192] chronic fatigue syndrome

[0193] premature ejaculation, DSM 302.75

[0194] erectile difficulty, DSM 302.72

[0195] anorexia nervosa, ICD 307.1, DSM 307.10

[0196] disorders of sleep, ICD 307.4

[0197] autism

[0198] mutism

[0199] trichotillomania

[0200] Anxiety and its frequent concomitant, panic disorder, may beparticularly mentioned in connection with the present compounds. Thesubject is carefully explained by the Diagnostic and Statistical Manualof Mental Disorders, published by the American Psychiatric Association,which classifies anxiety under its category 300.02.

[0201] In addition, the unique combination of pharmacological propertiespossessed by the compounds of formula I permit those compounds to beused in a method of simultaneously treating anxiety and depression. Theanxiety portion of the combined syndrome is believed to be attacked bythe 5HT-1_(A) receptor-affecting property of the compounds, and thedepression portion of the condition is believed to be addressed by theserotonin reuptake inhibition property. Thus, administration of aneffective amount, which is determined in an analogous manner asdiscussed hereinabove, of a compound of formula I, will provide a methodof simultaneously treating anxiety and depression.

[0202] It is well known that the chronic administration of nicotineresults in tolerance and, eventually, dependence. The use of tobacco hasbecome extremely widespread in all countries, despite the well knownadverse effects of the use of tobacco in all its forms. Thus, it isclear that tobacco use is extremely habit-forming, if not addictive, andthat its use provides sensations to the user which are pleasant andwelcome, even though the user may be fully aware of the drastic longterm ill effects of its use.

[0203] Recently, vigorous campaigns against the use of tobacco havetaken place, and it is now common knowledge that the cessation ofsmoking brings with it numerous unpleasant withdrawal symptoms, whichinclude irritability, anxiety, restlessness, lack of concentration,lightheadedness, insomnia, tremor, increased hunger and weight gain,and, of course, a craving for tobacco.

[0204] At the present time, probably the most widely used therapy toassist the cessation of tobacco use is nicotine replacement, by the useof nicotine chewing gum or nicotine-providing transdermal patches. It iswidely known, however, that nicotine replacement is less effectivewithout habit-modifying psychological treatment and training.

[0205] Thus, the present method of preventing or alleviating thesymptoms caused by withdrawal or partial withdrawal from the use oftobacco or of nicotine comprises the previously discussed method ofaffecting the serotonin 1_(A) receptor, in that the treatment methodcomprises the administration to a patient an effective amount of acompound of formula 1. The method of the present invention is broadlyuseful in assisting persons who want to cease or reduce their use oftobacco or nicotine. Most commonly, the form of tobacco use is smoking,most commonly the smoking of cigarettes. The present invention is alsohelpful, however, in assisting in breaking the habit of all types oftobacco smoking, as well as the use of snuff, chewing tobacco, etc. Thepresent method is also helpful to those who have replaced, or partiallyreplaced, their use of tobacco with the use of nicotine replacementtherapy. Thus, such patients can be assisted to reduce and eveneliminate entirely their dependence on nicotine in all forms.

[0206] A particular benefit of therapy with the present compounds is theelimination or reduction of the weight gain which very often resultsfrom reducing or withdrawing from use of tobacco or nicotine.

[0207] It will be understood that the present invention is useful forpreventing or alleviating the withdrawal symptoms which afflict patientswho are trying to eliminate or reduce their use of tobacco or nicotine.The common withdrawal symptoms of such people include, at least,irritability, anxiety, restlessness, lack of concentration, insomnia,nervous tremor, increased hunger and weight gain, light-headedness, andthe craving for tobacco or nicotine. The prevention or alleviation ofsuch symptoms, when they are caused by or occur in conjunction withceasing or reducing the patient's use of tobacco or nicotine is adesired result of the present invention and an important aspect thereof.

[0208] The invention is carried out by administering an effective amountof a compound of formula I to a patient who is in need of or carryingout a reduction or cessation of tobacco or nicotine use.

[0209] As used herein, the term “Patient” refers to a mammal such as adog, cat, guinea pig, mouse, rat, monkey, or human being. It isunderstood that a human being is the preferred patient.

[0210] As used herein, the terms “treating” or “to treat” each mean toalleviate symptoms, eliminate the causation either on a temporary orpermanent basis, or to prevent or slow the appearance of symptoms of thenamed disorder.

[0211] As used herein, the term “effective amount” refers to the amountof a compound of formula (I) which is effective, upon single or multipledose administration to a patient, in treating the patient suffering fromthe named disorder. The effective amount of compound to be administered,in general, is from about 1 to about 200 mg/day. The daily dose may beadministered in a single bolus, or in divided doses, depending on thejudgment of the physician in charge of the case. A more preferred rangeof doses is from about 5 to about 100 mg/day; other dosage ranges whichmay be preferred in certain circumstances are from about 10 to about 50mg/day; from about 5 to about 50 mg/day; from about 10 to about 25mg/day; and a particularly preferred range is from about 20 to about 25mg/day.

[0212] An effective amount can be readily determined by the attendingdiagnostician, as one skilled in the art, by the use of known techniquesand by observing results obtained under analogous circumstances. Indetermining the effective amount or dose, a number of factors areconsidered by the attending diagnostician, including, but not limitedto: the species of mammal; its size, age, and general health; thespecific disease or disorder involved; the degree of or involvement orthe severity of the disease or disorder; the response of the individualpatient; the particular compound administered; the mode ofadministration; the bioavailability characteristics of the preparationadministered; the dose regimen selected; the use of concomitantmedication; and other relevant circumstances.

[0213] In effecting treatment of a patient afflicted with a condition,disease or disorder described above, a compound of formula (I) can beadministered in any form or mode which makes the compound bioavailablein effective amounts, including oral and parenteral routes. For example,compounds of formula (I) can be administered orally, subcutaneously,intramuscularly, intravenously, transdermally, intranasally, rectally,and the like. Oral administration is generally preferred. One skilled inthe art of preparing formulations can readily select the proper form andmode of administration depending upon the particular characteristics ofthe compound selected, the disease state to be treated, the stage of thedisease, and other relevant circumstances.

[0214] It is understood that, while the compounds of formula Iindividually provide the benefit of the combination of serotoninreuptake inhibitors and serotonin 1A antagonists, it is entirelypossible to administer a compound of formula I in combination with aconventional serotonin reuptake inhibitor in order to obtain stillfurther enhanced results in potentiating serotonin reuptake inhibition.Examples of representative serotonin reuptake inhibitors include but arenot limited to the following:

[0215] Fluoxetine,N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine, is marketedin the hydrochloride salt form, and as the racemic mixture of its twoenantiomers. U.S. Pat. No. 4,314,081 is an early reference on thecompound. Robertson, et al., J. Med. Chem. 31, 1412 (1988), taught theseparation of the R and S enantiomers of fluoxetine and showed thattheir activity as serotonin uptake inhibitors is similar to each other.In this document, the word “fluoxetine” will be used to mean any acidaddition salt or the free base, and to include either the racemicmixture or either of the R and S enantiomers.

[0216] Duloxetine,N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine, is usuallyadministered as the hydrochloride salt and as the (+) enantiomer. It wasfirst taught by U.S. Pat. No. 4,956,388, which shows its high potency.The word “duloxetine” will be used here to refer to any acid additionsalt or the free base of the molecule.

[0217] Venlafaxine is known in the literature, and its method ofsynthesis and its activity as an inhibitor of serotonin andnorepinephrine uptake are taught by U.S. Pat. No. 4,761,501. Venlafaxineis identified as compound A in that patent.

[0218] Milnacipran(N,N-diethyl-2-aminomethyl-1-phenylcyclopropanecarboxamide) is taught byU.S. Pat. No. 4,478,836, which prepared milnacipran as its Example 4.The patent describes its compounds as antidepressants. Moret, et al.,Neuropharmacology 24,1211-19 (1985), describe its pharmacologicalactivities.

[0219] Citalopram,1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile,is disclosed in U.S. Pat. No. 4,136,193 as a serotonin reuptakeinhibitor. Its pharmacology was disclosed by Christensen, et al., Eur.J. Pharmacol. 41, 153 (1977), and reports of its clinical effectivenessin depression may be found in Dufour, et al., Int. Clin.Psychopharmacol. 2, 225 (1987), and Timmerman, et al., ibid., 239.

[0220] Fluvoxamine,5-methoxy-1-[4-(trifluoromethyl)phenyl]-1-pentanone-O-(2-aminoethyl)oxime,is taught by U.S. Pat. No. 4,085,225. Scientific articles about the drughave been published by Claassen, et al., Brit. J. Pharmacol. 60, 505(1977); and De Wilde, et al., J. Affective Disord. 4, 249 (1982); andBenfield, et al., Drugs 32, 313 (1986).

[0221] Sertraline, 1-(3,4-dichlorophenyl)-4-methylaminotetralin, isdisclosed in U.S. Pat. No. 4,536,518.

[0222] Paroxetine,trans-(−)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)piperidine,may be found in U.S. Pat. Nos. 3,912,743 and 4,007,196. Reports of thedrug's activity are in Lassen, Eur. J. Pharmacol. 47, 351 (1978);Hassan, et al., Brit. J. Clin. Pharmacol. 19, 705 (1985); Laursen, etal., Acta Psychiat. Scand. 71, 249 (1985); and Battegay, et al.,Neuropsychobiology 13, 31 (1985).

[0223] All of the U.S. patents which have been mentioned above inconnection with compounds used in the present invention are incorporatedherein by reference.

[0224] Fluoxetine or duloxetine are the preferred SRIs in pharmaceuticalcompositions combining a compound of formula I and an SRI, and thecorresponding methods of treatment.

[0225] It will be understood by the skilled reader that all of thecompounds used in the present invention are capable of forming salts,and that the salt forms of pharmaceuticals are commonly used, oftenbecause they are more readily crystallized and purified than are thefree bases. In all cases, the use of the pharmaceuticals described aboveas salts is contemplated in the description herein, and often ispreferred, and the pharmaceutically acceptable salts of all of thecompounds are included in the names of them.

[0226] The dosages of the drugs used in the present combination must, inthe final analysis, be set by the physician in charge of the case, usingknowledge of the drugs, the properties of the drugs in combination asdetermined in clinical trials, and the characteristics of the patient,including diseases other than that for which the physician is treatingthe patient. General outlines of the dosages, and some preferred humandosages, can and will be provided here. Dosage guidelines for some ofthe drugs will first be given separately; in order to create a guidelinefor any desired combination, one would choose the guidelines for each ofthe component drugs.

[0227] Fluoxetine: from about 1 to about 80 mg, once/day; preferred,from about 10 to about 40 mg once/day; preferred for bulimia andobsessive-compulsive disease, from about 20 to about 80 mg once/day;

[0228] Duloxetine: from about 1 to about 30 mg once/day; preferred, fromabout 5 to about 20 mg once/day;

[0229] Venlafaxine: from about 10 to about 150 mg once-thrice/day;preferred, from about 25 to about 125 mg thrice/day;

[0230] Milnacipran: from about 10 to about 100 mg once-twice/day;preferred, from about 25 to about 50 mg twice/day; Citalopram: fromabout 5 to about 50 mg once/day; preferred, from about 10 to about 30 mgonce/day;

[0231] Fluvoxamine: from about 20 to about 500 mg once/day; preferred,from about 50 to about 300 mg once/day;

[0232] Paroxetine: from about 5 to about 100 mg once/day; preferred,from about 50 to about 300 mg once/day.

[0233] In more general terms, one would create a combination of thepresent invention by choosing a dosage of SRI according to the spirit ofthe above guideline, and choosing a dosage of the compound of formula Iin the ranges taught above.

[0234] The adjunctive therapy of the present invention is carried out byadministering a SRI together with a compound of formula I in any mannerwhich provides effective levels of the two compounds in the body at thesame time. All of the compounds concerned are orally available and arenormally administered orally, and so oral administration of theadjunctive combination is preferred. They may be administered together,in a single dosage form, or may be administered separately.

[0235] However, oral administration is not the only route or even theonly preferred route. For example, transdermal administration may bevery desirable for patients who are forgetful or petulant about takingoral medicine. One of the drugs may be administered by one route, suchas oral, and the other may be administered by the trans-dermal,percutaneous, intravenous, intramuscular, intranasal or intrarectalroute, in particular circumstances. The route of administration may bevaried in any way, limited by the physical properties of the drugs andthe convenience of the patient and the caregiver.

[0236] It is particularly preferred, however, for the adjunctivecombination to be administered as a single pharmaceutical composition,and so pharmaceutical compositions incorporating both a SRI and acompound of formula I are important embodiments of the presentinvention. Such compositions may take any physical form which ispharmaceutically acceptable, but orally usable pharmaceuticalcompositions are particularly preferred. Such adjunctive pharmaceuticalcompositions contain an effective amount of each of the compounds, whicheffective amount is related to the daily dose of the compounds to beadministered. Each adjunctive dosage unit may contain the daily doses ofboth compounds, or may contain a fraction of the daily doses, such asone-third of the doses. Alternatively, each dosage unit may contain theentire dose of one of the compounds, and a fraction of the dose of theother compound. In such case, the patient would daily take one of thecombination dosage units, and one or more units containing only theother compound. The amounts of each drug to be contained in each dosageunit depends on the identity of the drugs chosen for the therapy, andother factors such as the indication for which the adjunctive therapy isbeing given.

[0237] As stated above, the benefit of the adjunctive therapy is itsability to augment the increase in availability of serotonin,norepinephrine and dopamine caused by the SRI compounds, resulting inimproved activity in treating the various conditions described below indetail. The increase in availability of serotonin is particularlyimportant and is a preferred aspect of the invention. Further, theinvention provides a more rapid onset of action than is usually providedby treatment with the SRI alone.

[0238] Pharmaceutical Compositions

[0239] The present invention provides pharmaceutical compositions ofcompounds of formula I, including the hydrates thereof, comprising, asan active ingredient, a compound of formula I in admixture or otherwisein association with one or more pharmaceutically acceptable carriers,diluents or excipients. It is customary to formulate pharmaceuticals foradministration, to provide control of the dosage and stability of theproduct in shipment and storage, and the usual methods of formulationare entirely applicable to the compounds of formula I. Suchpharmaceutical compositions are valuable and novel because of thepresence of the compounds of formula I therein. Although pharmaceuticalchemists are well aware of many effective ways to formulatepharmaceuticals, which technology is applicable to the presentcompounds, some discussion of the subject will be given here for theconvenience of the reader.

[0240] The usual methods of formulation used in pharmaceutical scienceand the usual types of compositions may be used according to the presentinvention, including tablets, chewable tablets, capsules, solutions,parenteral solutions, intranasal sprays or powders, troches,suppositories, transdermal patches and suspensions. In general,pharmaceutical compositions contain from about 0.5% to about 50% of thecompound of formula (I) in total, depending on the desired dose and thetype of composition to be used. The amount of the compound of formula(I), however, is best defined as the effective amount, that is, theamount of each compound which provides the desired dose to the patientin need of such treatment. The activity of the compounds do not dependon the nature of the composition, so the compositions are chosen andformulated solely for convenience and economy. Any compound may beformulated in any desired form of composition. Some discussion ofdifferent compositions will be provided, followed by some typicalformulations.

[0241] Capsules are prepared by mixing the compound with a suitablediluent and filling the proper amount of the mixture in capsules. Theusual diluents include inert powdered substances such as starch of manydifferent kinds, powdered cellulose, especially crystalline andmicrocrystalline cellulose, sugars such as fructose, mannitol andsucrose, grain flours and similar edible powders.

[0242] Tablets are prepared by direct compression, by wet granulation,or by dry granulation. Their formulations usually incorporate diluents,binders, lubricants and disintegrators as well as the compound. Typicaldiluents include, for example, various types of starch, lactose,mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such assodium chloride and powdered sugar. Powdered cellulose derivatives arealso useful. Typical tablet binders are substances such as starch,gelatin and sugars such as lactose, fructose, glucose and the like.Natural and synthetic gums are also convenient, including acacia,alginates, methylcellulose, polyvinylpyrrolidine and the like.Polyethylene glycol, ethylcellulose and waxes can also serve as binders.

[0243] A lubricant is necessary in a tablet formulation to prevent thetablet and punches from sticking in the die. The lubricant is chosenfrom such slippery solids as talc, magnesium and calcium stearate,stearic acid and hydrogenated vegetable oils.

[0244] Tablet disintegrators are substances which swell when wetted tobreak up the tablet and release the compound. They include starches,clays, celluloses, algins and gums. More particularly, corn and potatostarches, methylcellulose, agar, bentonite, wood cellulose, powderednatural sponge, cation-exchange resins, alginic acid, guar gum, citruspulp and carboxymethylcellulose, for example, may be used, as well assodium lauryl sulfate.

[0245] Enteric formulations are often used to protect an activeingredient from the strongly acidic contents of the stomach. Suchformulations are created by coating a solid dosage form with a film of apolymer which is insoluble in acidic environments, and soluble in basicenvironments. Exemplary films are cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methylcellulose phthalate andhydroxypropyl methylcellulose acetate succinate. Tablets are oftencoated with sugar as a flavor and sealant, or with film-formingprotecting agents to modify the dissolution properties of the tablet.The compounds may also be formulated as chewable tablets, by using largeamounts of pleasant-tasting substances such as mannitol in theformulation, as is now well-established practice. Instantly dissolvingtablet-like formulations are also now frequently used to assure that thepatient consumes the dosage form, and to avoid the difficulty inswallowing solid objects that bothers some patients.

[0246] When it is desired to administer the combination as asuppository, the usual bases may be used. Cocoa butter is a traditionalsuppository base, which may be modified by addition of waxes to raiseits melting point slightly. Water-miscible suppository bases comprising,particularly, polyethylene glycols of various molecular weights are inwide use, also.

[0247] Transdermal patches have become popular recently. Typically theycomprise a resinous composition in which the drugs will dissolve, orpartially dissolve, which is held in contact with the skin by a filmwhich protects the composition. Many patents have appeared in the fieldrecently. Other, more complicated patch compositions are also in use,particularly those having a membrane pierced with pores through whichthe drugs are pumped by osmotic action.

[0248] The following typical formulae are provided for the interest andinformation of the pharmaceutical scientist.

Formulation 1

[0249] Hard gelatin capsules are prepared using the followingingredients: Quantity (mg/capsule) Example #1  20 mg Starch, dried 200mg Magnesium stearate  10 mg Total 230 mg

[0250] As with any group of structurally related compounds which possessa particular generic utility, certain groups and configurations arepreferred for compounds of formula I or formula Ia.

[0251] With respect to substituent R¹, compounds wherein R¹ is hydrogen,F, methyl, ethyl, —C(═O)NR⁸R⁹, or CN are preferred, with hydrogen,methyl, and —C(═O)NH₂ being especially preferred.

[0252] With respect to substitunet R², compounds wherein R² is hydrogenare preferred

[0253] With respect to substituent A, compounds wherein A is hydroxy arepreferred. In addition, it is further preferred that when A is hydroxy,it is in the (S)-configuration.

[0254] With respect to substituent m, compounds wherein m is 1 or 2 arepreferred.

[0255] With respect to substituent n, compounds wherein n is 1 or 2 arepreferred.

[0256] With respect to substituents p and q, compounds wherein p and qare both one are preferred.

[0257] With respect to substituent X, compounds wherein X is hydrogenare preferred.

[0258] With respect to Y, compounds wherein Y is S are preferred.

[0259] With respect to substituent R³, compounds wherein R³ is hydrogen,methyl, ethyl or propyl are preferred.

[0260] With respect to substituent R⁴, compounds wherein R⁴ is hydrogen,methyl, ethyl or propyl are preferred.

[0261] With respect to substituent R⁵, compounds wherein R⁵ is hydrogen,F, Cl, Br, I OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, halo(C₁-C₆) alkyl, phenyl,substituted phenyl, C(═O)NR₈R₉, NO₂, NH₂, and CN are preferred, withhydrogen, F, Cl, Br, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy,propoxy and isopropoxy being especially preferred.

[0262] With respect to substituent R⁶, compounds wherein R⁶ is hydrogen,F, Cl, Br, I OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, halo(C₁-C₆) alkyl, phenyl,substituted phenyl, C(═O)NR₈R₉, NO₂, NH₂, and CN are preferred, withhydrogen, F, Cl, Br, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy,propoxy and isopropoxy being especially preferred.

[0263] With respect to substituent R⁷, compounds wherein R⁷ is hydrogen,F, Cl, Br, methyl, ethyl, propyl, isopropyl or butyl are preferred, withmethyl, ethyl, and propyl being especially preferred.

[0264] With respect to substituent R⁸, compounds wherein R⁸ is hydrogen,methyl, ethyl, propyl, isopropyl or butyl are preferred.

[0265] With respect to substituent R⁹, compounds wherein R⁹ is hydrogen,methyl, ethyl, propyl, isopropyl or butyl are preferred.

[0266] With respect to the piperidine portion of formula I, compoundswith the following substitutions are preferred:

[0267]  including the individual enantiomers thereof.

[0268] With respect to substituent B, compounds with the followingsubstitutions are preferred:

[0269] More specifically, as shown in Table 1, the followingsubstituents represented by B are especially preferred: TABLE ISubstituent B A

B

C

D

E

F

G

h

i

j

k

l

m

n

o

p

q

r

s

t

u

v

w

x

y

z

aa

bb

cc

dd

ee

ff

gg

hh

ii

jj

kk

ll

mm

nn

oo

pp

qq

rr

tt

uu

vv

ww

xx

We claim:
 1. A compound of the formula:

wherein A is hydrogen, OH or (C₁-C₆) alkoxy: B is selected from thegroup consisting of:

represents a single or a double bond; X is hydrogen, OH or C₁-C₆ alkoxywhen

represents a single bond in the piperidine ring, and X is nothing when

represents a double bond in the piperidine ring; Y is S or CH₂; R¹ ishydrogen, F, C₁-C₂₀ alkyl, —C(═O)NR⁸R⁹, or CN; R² is hydrogen, F, Cl,Br, I, OH, C₁-C₆ alkyl or C₁-C₆ alkoxy; R³ and R⁴ are each independentlyhydrogen or C₁-C₄ alkyl; R⁵ and R⁶ are each independently hydrogen, F,Cl, Br, I, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, halo(C₁-C₆)alkyl, phenyl,—C(═O)NR⁸R⁹, NO₂, NH₂, CN, or phenyl substituted with from 1 to 3substituents selected from the group consisting of F, Cl, Br, I, OH,C₁-C₆ alkyl, C₁-C₆ alkoxy, halo(C₁-C₆)alkyl, NO₂, NH₂, CN, and phenyl;R⁷ is hydrogen, F, Cl, Br, I, OH, C₁-C₆ alkyl or (C₁-C₆ alkyl)NR⁸R⁹; R⁸and R⁹ are each independently hydrogen or C₁-C₁₀ alkyl; m is 0, 1, or 2;n is 0, 1, or 2; p is 0, 1, 2, 3 or 4; and q is 0, 1, 2 or 3; or apharmaceutically acceptable salt thereof.
 2. A compound of the formula:

wherein B is selected from the group consisting of:

represents a single or a double bond; X is hydrogen, OH or C₁-C₆ alkoxywhen

represents a single bond in the piperidine ring, and X is nothing when

represents a double bond in the piperidine ring; Y is S or CH₂; R¹ ishydrogen, F, C₁-C₂₀ alkyl, —C(═O)NR⁸R⁹, or CN; R² is hydrogen, F, Cl,Br, I, OH, C₁-C₆ alkyl or C₁-C₆ alkoxy; R³ and R⁴ are each independentlyhydrogen or C₁-C₄ alkyl; R⁵ and R⁶ are each independently hydrogen, F,Cl, Br, I, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, halo(C₁-C₆)alkyl, phenyl,—C(═O)NR⁸R9, NO₂, NH₂, CN, or phenyl substituted with from 1 to 3substituents selected from the group consisting of F, Cl, Br, I, OH,C₁-C₆ alkyl, C₁-C₆ alkoxy, halo(C₁-C₆)alkyl, NO₂, NH₂, CN, and phenyl;R⁷ is hydrogen, F, Cl, Br, I, OH, C₁-C₆ alkyl or (C₁-C₆ alkyl)NR⁸R⁹; R⁸and R⁹ are each independently hydrogen or C₁-C₁₀ alkyl; m is 0, 1, or 2;and n is 0, 1, or 2; or a pharmaceutically acceptable salt thereof.
 3. Acompound according to claim 2 wherein Y is S.
 4. A compound according toclaim 3 wherein R² is hydrogen.
 5. A compound according to any one ofclaims 2 to 4 wherein R¹ is hydrogen, methyl, or —C(═O)NH₂.
 6. Acompound according to any one of claims 2 to 5 wherein X is hydrogen. 7.A compound according to any one of claims 2 to 6 wherein R¹ is hydrogenor methyl.
 8. A compound according to any one of claims 2 to 7 wherein mis 0 and n is
 1. 9. A compound according to any one of claims 2 to 8wherein R³ is hydrogen and R⁴ is methyl.
 10. A compound according to anyone of claims 2 to 7 wherein m is 0 and n is
 0. 11. A compound accordingto any one of claims 2 to 10 wherein B is:


12. A compound according to claim 11 wherein R⁷ is methyl, ethyl, orpropyl, and R⁵ and R⁶ are hydrogen.
 13. A method of inhibiting thereuptake of serotonin and antagonizing the 5-HT_(1A) receptor whichcomprises administering to a patient in need of such treatment aneffective amount of a compound of the formula:

wherein A is hydrogen or OH: B is selected from the group consisting of:

represents a single or a double bond; X is hydrogen, OH or C₁-C₆ alkoxywhen

represents a single bond in the piperidine ring, and X is nothing when

represents a double bond piperidine ring; R¹ is hydrogen, F, C₁-C₂₀alkyl, —C(═O)NR⁸R⁹, or CN; R² is hydrogen, F, Cl, Br, 1, OH, C₁-C₆ alkylor C₁-C₆ alkoxy; R³ and R⁴ are each independently hydrogen or C₁-C₄alkyl; R⁵ and R⁶ are each independently hydrogen, F, Cl, Br, 1, OH,C₁-C₆ alkyl, C₁-C₆ alkoxy, halo(C₁-C₆)alkyl, phenyl, —C(═O)NR⁸R⁹, NO₂,NH₂, CN, or phenyl substituted with from 1 to 3 substituents selectedfrom the group consisting of F, Cl, Br, 1, OH, C₁-C₆ alkyl, C₁-C₆alkoxy, halo(C₁-C₆)alkyl, NO₂, NH₂, CN, and phenyl; R⁷ is hydrogen, F,Cl, Br, 1, OH, C₁-C₆ alkyl or (C₁-C₆ alkyl)NR⁸R⁹; R⁸ and R⁹ are eachindependently hydrogen or C₁-C₁₀ alkyl; m is 0, 1, or 2; n is 0, 1, or2; p is 0, 1, 2, 3 or 4; and q is 0, 1, 2 or 3; or a pharmaceuticallyacceptable salt thereof; with the proviso that if both R³ and R⁴represent hydrogen, then R¹ is F, C₁-C₂₀ alkyl, —C(═O)NR⁸R⁹, or CN. 14.A method of potentiating the action of a serotonin reuptake inhibitorcomprising administering to a patient in of such treatment a compoundformula:

wherein A is hydrogen or OH: B is selected from the group consisting of:

represents a single or a double bond; X is hydrogen, OH or C₁-C₆ alkoxywhen

represents a single bond in the piperidine ring, and X is nothing when

represents a double bond piperidine ring; R¹ is hydrogen, F, C₁-C₂₀alkyl, —C(═O)NR⁸R⁹, or CN; R² is hydrogen, F, Cl, Br, I, OH, C₁-C₆ alkylor C₁-C₆ alkoxy; R³ and R⁴ are each independently hydrogen or C₁-C₄alkyl; R⁵ and R6 are each independently hydrogen, F, Cl, Br, 1, OH,C₁-C₆ alkyl, C₁-C₆ alkoxy, halo(C₁-C₆)alkyl, phenyl, —C(—O)NR⁸R⁹, NO₂,NH₂, CN, or phenyl substituted with from 1 to 3 substituents selectedfrom the group consisting of F, Cl, Br, 1, OH, C₁-C₆ alkyl, C₁-C₆alkoxy, halo(C₁-C₆)alkyl, NO₂, NH₂, CN, and phenyl; R⁷ is hydrogen, F,Cl, Br, 1, OH, C₁-C₆ alkyl or (C₁-C₆ alkyl)NR⁸R⁹; R⁸ and R⁹ are eachindependently hydrogen or C₁-C₁₀ alkyl; m is 0, 1, or 2; n is 0, 1, or2; p is 0, 1, 2, 3 or 4; and q is 0, 1, 2 or 3; or a pharmaceuticallyacceptable salt thereof; with the proviso that if both R³ and R⁴represent hydrogen, then R¹ is F, C₁-C₂₀ alkyl, —C(═O)NR⁸R⁹, or CN. 15.A method of treating depression comprising administering to a patient inneed thereof an effective amount of a compound of formula:

wherein A is hydrogen or OH: B is selected from the group consisting of:

represents a single or a double bond; X is hydrogen, OH or C₁-C₆ alkoxywhen

represents a single bond in the piperidine ring, and X is nothing when

represents a double bond piperidine ring; R¹ is hydrogen, F, C₁-C₂₀alkyl, —C(═O)NR⁸R⁹, or CN; R² is hydrogen, F, Cl, Br, 1, OH, C₁-C₆ alkylor C₁-C₆ alkoxy; R³ and R⁴ are each independently hydrogen or C₁-C₄alkyl; R⁵ and R⁶ are each independently hydrogen, F, Cl, Br, 1, OH,C₁-C₆ alkyl, C₁-C₆ alkoxy, halo(C₁-C₆)alkyl, phenyl, —C(═O)NR⁸R⁹, NO₂,NH₂, CN, or phenyl substituted with from 1 to 3 substituents selectedfrom the group consisting of F, Cl, Br, 1, OH, C₁-C₆ alkyl, C₁-C₆alkoxy, halo(C₁-C₆)alkyl, NO₂, NH₂, CN, and phenyl; R⁷ is hydrogen, F,Cl, Br, 1, OH, C₁-C₆ alkyl or (C₁-C₆ alkyl)NR⁸R⁹; R⁸ and R⁹ are eachindependently hydrogen or C₁-C₁₀ alkyl; m is 0, 1, or 2; n is 0, 1, or2; p is 0, 1, 2, 3 or 4; and q is 0, 1, 2 or 3; or a pharmaceuticallyacceptable salt thereof; with the proviso that if both R³ and R⁴represent hydrogen, then R¹ is F, C₁-C₂₀ alkyl, —C(═O)NR⁸R⁹, or CN. 16.A pharmaceutical composition comprising an effective amount of acompound according to any one of claims 1 to 12 in combination with apharmaceutically acceptable carrier, diluent or excipient.
 17. The useof a compound according to claim 1 for the manufacture of a medicamentfor inhibiting the reuptake of serotonin and antagonizing the 5-HT_(1A)receptor.
 18. The use of a compound according to claim 1 for inhibitingthe reuptake of serotonin, and antagonizing the 5-HT_(1A) receptor. 19.The use of a compound according to claim 1 for the manufacture of amedicament for treating depression.